6,5-Heterocyclic Propargylic Alcohol Compounds and Uses Therefor

ABSTRACT

The invention relates to novel compounds of Formula I: 
     
       
         
         
             
             
         
       
     
     wherein A, Y, R 1 , R 2  and the subscript b each has the meaning as described herein and compounds of Formula I, and stereoisomers, geometric isomers, tautomers, solvates, metabolites, isotopes, pharmaceutically acceptable salts, or prodrugs thereof. Compounds of Formula I and pharmaceutical compositions thereof are useful in the treatment of disease and disorders in which undesired or over-activation of NF-kB signaling is observed.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. application Ser. No.13/420,988, filed on Mar. 15, 2012, which claims the benefit of priorityto U.S. Provisional Application No. 61/453,494, filed on Mar. 16, 2011,each of which is incorporated by reference in its entirety for allpurposes.

FIELD OF THE INVENTION

The present invention relates to organic compounds useful for therapyand/or prophylaxis in a mammal, and in particular to inhibitors ofNF-kB-inducing kinase (NIK) useful for treating cancer and inflammatorydiseases and disorders, among others. NF-kB inducing kinase (NIK) isalso known as MAPK kinase kinase 14 (MAP3K14) and is a serine/threoninekinase and a member of the MAPK family. It was originally identified ina two-hybrid screen as a binding partner of TNF receptor (TNFR)associated factor 2 (TRAF2) [See, Malinin, N L, et al, Nature, 1997,385:540-4]. Overexpression of NIK leads to the activation of NF-kB anddominant negative forms of NIK lacking kinase activity were able toinhibit NF-kB activation in response to TNF and IL-1 treatment. Thus NIKhas been identified as an important component of the NF-kB signalingpathway. Scientific research has shown that in blocking the NF-kBsignaling pathway in cancer cells can cause such cells to stopproliferating, to die, and/or to become more sensitive to the action ofother anti-cancer therapies. Additionally, research has shown that NF-κBcontrols the expression of many genes involved in inflammation and thatNF-kB signalling is found to be chronically active in many inflammatorydiseases, such as rheumatoid arthritis, inflammatory bowel disease,arthritis, sepsis, gastritis, asthma, among others. Accordingly, organiccompounds capable of inhibiting NIK and thereby inhibiting, weakeningand/or lessening the undesired or over-activation of the NF-kB signalingpathway can have a therapeutic benefit for the treatment diseases anddisorders for which such undesired or over-activation of NF-kB signalingis observed.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides for compounds of FormulaI:

in which for compounds of Formula I, Y is nitrogen and the subscript bis the integer 0, or Y is carbon and the subscript b is the integer 1.R¹ is C₁₋₂ alkyl, C₁₋₂ haloalkyl or —CH₂—OH. R² is C₁₋₆ alkyl, C₁₋₆haloalkyl, 3-7 membered cycloalkyl, C₁₋₆ alkylene-3-7 memberedcycloalkyl, phenyl, 5-6 membered heteroaryl, —C(═O)R^(x2a),—C(═O)OR^(x2a) or —C(═O)NR^(x2a)R^(x2b), in which R^(x2a) is selectedfrom the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ heteroalkyl, 3-8 membered cycloalkyl, 3-8 memberedheteroalkyl, —(C₁₋₆ alkylene)-(3-8 membered cycloalkyl), —(C₁₋₆alkylene)-(3-8 membered heterocycloalkyl), —(C₁₋₆ alkylene)-(6-memberedaryl) and —(C₁₋₆ alkylene)-(5-6 membered heteroaryl), and R^(x2b) isselected from the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl and C₁₋₆ heteroalkyl. In Formula I, when R^(x2a)and R^(x2b) are attached to the same nitrogen atom, then they areoptionally combined to form a 3-7 membered heterocycloalkyl furthercomprising 0-2 additional heteroatoms selected from N, O and S.Alternatively, in Formula I, R¹ and R² are combined to form a 3-8membered cycloalkyl or 3-8 membered heterocycloalkyl and optionallyfused thereto is a 5-6 membered heteroaryl ring comprising 1-3heteroatoms selected from N, O and S. The aliphatic and/or aromaticportions of R¹ and R² either independently or when combined, areoptionally substituted with 1 to 5 R^(R1/2) substitutents selectedfrom/the group consisting of F, Cl, Br, I, —OH, —NH₂, —SH, —CF₃, —OCF₃,—SF₅, —OCH₃, —(X^(a))₀₋₁—CN, —(X^(a))₀₋₁—NO₂, —(X^(a))₀₋₁—N₃,—(X^(a))₀₋₁—OH, —(X^(a))₀₋₁—H, —(X^(a))₀₋₁—OR^(a),—(X^(a))₀₋₁—N(H)R^(a), —(X^(a))₀₋₁—N(H)₂, —(X^(a))₀₋₁—N(R^(a))₂,—(X^(a))₀₋₁—SR^(a), —(X^(a))₀₋₁—SH, —(X^(a))₀₋₁—C(O)R^(a),—(X^(a))₀₋₁—S(O)₂R^(a), —(X^(a))₀₋₁—S(O)R^(a),—(X^(a))₀₋₁—N(H)S(O)₂R^(a), —(X^(a))₀₋₁—N(R^(a))S(O)₂R^(a),—(X^(a))₀₋₁—OC(O)R^(a), —(X^(a))₀₋₁—N(H)C(O)OR^(a),—(X^(a))₀₋₁—N(R^(a))C(O)OR^(a), —(X^(a))₀₋₁—C(═O)OR^(a),—(X^(a))₀₋₁—C(═O)OH, —(X^(a))₀₋₁—C(═O)N(H)R^(a),—(X^(a))₀₋₁—C(═O)N(R^(a))R^(a), —(X^(a))₀₋₁—N(H)C(═O)R^(a),—(X^(a))₀₋₁—N(R^(a))C(═O)R^(a), —(X^(a))₀₋₁—N(H)C(═O)OR^(a) and—(X^(a))₀₋₁—N(R^(a))C(═O)OR^(a), in which X^(a) is selected from thegroup consisting of C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene,C₁₋₆ heteroalkylene, 3-6 membered cycloalkylene and 3-6 memberedheterocycloalkylene, and R^(a) at each occurrence is independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆heteroalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3-7 membered cycloalkyl and 3-7membered heterocycloalkyl. In Formula I, A is selected from the groupconsisting of:

in which X¹, X² and X³ are independently N or CR⁵, wherein at least oneof X¹, X² and X³ is CR⁵, where R⁵ is selected from the group consistingof hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, halogen, —OC₁₋₆ alkyl, 3-6membered heterocycloalkyl-C₁₋₃alkyleneoxy-, —CN, —NO₂, —NH(C₁₋₆ alkyl),—NH₂ and —N(C₁₋₆ alkyl)₂. In Formula I, R³ is 5-10 membered heteroaryloptionally substituted with —NR^(x3a)R^(x3b), in which R^(x3a) andR^(x3b) are each independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ heteroalkyl, 6-10 membered aryl and 5-10 memberedheteroaryl. In Formula I, R³ and the R^(x3a) and R^(x3b) groups of R³,if present, are further each independently optionally substituted with 1to 5 R^(R3) substituents selected from the group consisting of F, Cl,Br, I, —OH, —NH₂, —SH, —CF₃, —OCF₃, —SF₅, —OCH₃, —(X^(b))₀₋₁—CN,—(X^(b))₀₋₄—NO₂, —(X^(b))₀₋₁—N₃, —(X^(b))—OH, —(X^(b))—H,—(X^(b))₀₋₁—OR^(b), —(X^(b))₀₋₁—N(H)R^(b), —(X^(b))—N(H)₂,—(X^(b))₀₋₁—N(R^(b))₂, —(X^(b))₀₋₁—SR^(b), —(X^(b))₀₋₁—SH,—(X^(b))₀₋₁—C(O)R^(b), —(X^(b))₀₋₁—S(O)₂R^(b)—(X^(b))₀₋₁—S(O)R^(b),—(X^(b))₀₋₁—N(H)S(O)₂R^(b), —(X^(b))₀₋₁—N(R^(b))S(O)₂R^(b),—(X^(b))₀₋₁—C(O)R^(b), —(X^(b))₀₋₁—N(H)C(O)OR^(b),—(X^(b))₀₋₁—N(R^(b))C(O)OR^(b), —(X^(b))₀₋₁—C(═O)OR^(b),—(X^(b))₀₋₁—C(═O)OH, —(X^(b))₀₋₁—C(═O)N(H)R^(b),—(X^(b))₀₋₁—C(═O)N(R^(b))R^(b), —(X^(b))₀₋₁—N(H)C(═O)R^(b),—(X^(b))₀₋₁—N(R^(b))C(═O)R^(b), —(X^(b))₀₋₁—N(H)C(═O)OR^(b) and—(X^(b))₀₋₁—N(R^(b))C(═O)OR^(b), in which X^(b) is selected from thegroup consisting of C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene,C₁₋₆ heteroalkylene, C₃₋₆ cycloalkylene and C₃₋₆ heterocycloalkylene,and R^(b) at each occurrence is independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ heteroalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 3-7 membered cycloalkyl and 3-7 memberedheterocycloalkyl. In Formula I, R⁴ is -(L)₀₋₁-lea, where L is selectedfrom the group consisting of —O—, —N(H)—, —C(═O)—, C₁₋₄ alkylene, C₁₋₄haloalkylene, C₂₋₄ alkenylene, C₂₋₄ alkynylene and C₁₋₄ heteroalkyleneand R^(x4a) is selected from the group consisting of hydrogen, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ heteroalkyl,3-6 membered cycloalkyl, 3-9 membered heterocycloalkyl, 6-10 memberedaryl and 5-10 membered heteroaryl. The aliphatic or aromatic portions ofR⁴ are independently substituted with 0 to 5 R⁴ substituents selectedfrom the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆heteroalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₃₋₆heterocycloalkyl, F, Cl, Br, I, —OH, —NH₂, —SH, —CF₃, —OCF₃, —SF₅,—(X^(c))₀₋₁—CN, —(X^(c))₀₋₁—NO₂, —(X^(c))₀₋₁—N₃, —(X^(c))—OH,—(X^(c))₀₋₁—OR^(c), —(X^(c))—H, —(X^(c))₀₋₁—R^(c),—(X^(c))₀₋₁—N(H)R^(c), —(X^(c))₀₋₁—N(R^(c))₂, —(X^(c))₀₋₁—SR^(c),—(X^(c))₀₋₁—C(O)R^(c), —(X^(c))₀₋₁—S(O)₂R^(c), —(X^(c))₀₋₁—S(O)R^(c),—(X^(c))₀₋₁—N(H)S(O)₂R^(c), —(X^(c))₀₋₁—N(R^(c))S(O)₂R^(c),—(X^(c))₀₋₁—C(═O)OR^(c), —(X^(c))₀₋₁—C(═O)OH,—(X^(c))₀₋₁—C(═O)N(H)R^(c)), —(X^(c))₀₋₁—C(═O)N(R^(c))R^(c),—(X^(c))₀₋₁—N(H)C(═O)R^(c) and —(X^(c))₀₋₁—N(R^(c))C(═O)R^(c), in whichX^(c) is selected from the group consisting of C₁₋₆ alkylene, C₂₋₆alkenylene, C₂₋₆ alkynylene, C₁₋₆ heteroalkylene, C₃₋₆ cycloalkylene andC₃₋₆ heterocycloalkylene, and R^(c) at each occurrence is independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆heteroalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3-7 membered cycloalkyl, 3-7membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl. InFormula I, any two R^(c) groups attached to the same nitrogen atom areoptionally combined to form a 3-7 membered heterocycloalkyl or 5-10membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S.In another aspect, the invention provides for stereoisomers, geometricisomers, tautomers, solvates, metabolites, isotopes, pharmaceuticallyacceptable salts, or prodrugs of compound of Formula I. In anotheraspect, the invention provides for pharmaceutical compositionscomprising a compound of Formula I (or stereoisomers, geometric isomers,tautomers, solvates, metabolites, isotopes, pharmaceutically acceptablesalts, or prodrugs thereof) and a therapeutically inert carrier. Inanother aspect, the invention provides for a method (and/or use) ofcompounds of Formula I in the treatment of diseases and disorders, suchas, for example, cancer, inflammatory diseases, autoimmune diseases,among others. In another aspect, the invention provides for compounds ofFormula I for the preparation of a medicament for the treatment ofcancer, inflammatory diseases, autoimmune diseases, among others. Inanother aspect, the inventions provides for compounds of Formula I forthe treatment of diseases and disorders, including, cancer, inflammatorydisease, autoimmune disease, among others.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides for compounds of Formula I, pharmaceuticalcompositions comprising compounds of Formula I and methods of using suchcompounds and compositions in treating diseases and disordered relatedto undesired or overactivation of NF-kB signaling pathway, such as, forexample, certain cancers and inflammatory diseases and disorders.

DEFINITIONS

As used herein, the term “alkyl”, by itself or as part of anothersubstituent, means, unless otherwise stated, a straight or branchedchain hydrocarbon radical, having the number of carbon atoms designated(i.e., C_(1-g) means one to eight carbons). Examples of alkyl groupsinclude methyl, ethyl, n-propyl, iso-propyl, n-butyl, t-butyl,iso-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and thelike. The term “alkenyl” refers to an unsaturated alkyl radical havingone or more double bonds. Similarly, the term “alkynyl” refers to anunsaturated alkyl radical having one or more triple bonds. Examples ofsuch unsaturated alkyl groups include vinyl, 2-propenyl, crotyl,2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl),ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs andisomers. The term “cycloalkyl,” “carbocyclic,” or “carbocycle” refers tohydrocarbon rings having the indicated number of ring atoms (e.g., 3-6membered cycloalkyl) and being fully saturated or having no more thanone double bond between ring vertices. As used herein, “cycloalkyl,”“carbocyclic,” or “carbocycle” is also meant to refer to bicyclic,polycyclic and spirocyclic hydrocarbon rings such as, for example,bicyclo[2.2.1]heptane, pinane, bicyclo[2.2.2]octane, adamantane,norborene, spirocyclic C₅₋₁₂ alkane, etc. As used herein, the terms,“alkenyl,” “alkynyl,” “cycloalkyl,”, “carbocycle,” and “carbocyclic,”are meant to include mono and polyhalogenated variants thereof.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chainhydrocarbon radical, consisting of the stated number of carbon atoms andfrom one to three heteroatoms selected from the group consisting of O,N, Si and S, and wherein the nitrogen and sulfur atoms can optionally beoxidized and the nitrogen heteroatom can optionally be quaternized. Theheteroatom(s) O, N and S can be placed at any interior position of theheteroalkyl group. The heteroatom Si can be placed at any position ofthe heteroalkyl group, including the position at which the alkyl groupis attached to the remainder of the molecule. A “heteroalkyl” cancontain up to three units of unsaturation, and also include mono- andpoly-halogenated variants, or combinations thereof. Examples include—CH₂—CH₂—O—CH₃, —CH₂—CH₂—O—CF₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃,—CH₂—CH═N—OCH₃, and CH═CH═N(CH₃)—CH₃. Up to two heteroatoms can beconsecutive, such as, for example, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃.

The term “heterocycloalkyl,” “heterocyclic,” or “heterocycle” refers toa cycloalkane ring having the indicated number of ring atoms (e.g., 5-6membered heterocycloalkyl) that contain from one to five heteroatomsselected from N, O, and S, wherein the nitrogen and sulfur atoms areoptionally oxidized, nitrogen atom(s) are optionally quaternized, asring atoms. Unless otherwise stated, a “heterocycloalkyl,”“heterocyclic,” or “heterocycle” ring can be a monocyclic, a bicyclic,spirocyclic or a polycylic ring system. Non limiting examples of“heterocycloalkyl,” “heterocyclic,” or “heterocycle” rings includepyrrolidine, piperidine, N-methylpiperidine, imidazolidine,pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin,dioxolane, phthalimide, piperidine, pyrimidine-2,4(1H,3H)-dione,1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-5-oxide,thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline,thiopyran, pyrone, tetrahydrofuran, tetrhydrothiophene, quinuclidine,tropane and the like. A “heterocycloalkyl,” “heterocyclic,” or“heterocycle” group can be attached to the remainder of the moleculethrough one or more ring carbons or heteroatoms. A “heterocycloalkyl,”“heterocyclic,” or “heterocycle” can include mono- and poly-halogenatedvariants thereof.

The term “alkylene” by itself or as part of another substituent means adivalent radical derived from an alkane, as exemplified by—CH₂CH₂CH₂CH₂—. Typically, an alkyl (or alkylene) group will have from 1to 24 carbon atoms, with those groups having 10 or fewer carbon atomsbeing preferred in the present invention. “Alkenylene” and “alkynylene”refer to the unsaturated forms of “alkylene” having double or triplebonds, respectively. “Alkylene”, “alkenylene” and “alkynylene” are alsomeant to include mono and poly-halogenated variants.

The term “heteroalkylene” by itself or as part of another substituentmeans a divalent radical, saturated or unsaturated or polyunsaturated,derived from heteroalkyl, as exemplified by —CH₂—CH₂—S—CH₂CH₂— and—CH₂—S—CH₂—CH₂—NH—CH₂—, —O—CH₂—CH═CH—, —CH₂—CH═C(H)CH₂—O—CH₂— andS—CH₂—C≡C—. For heteroalkylene groups, heteroatoms can also occupyeither or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy,alkyleneamino, alkylenediamino, and the like). The term “heteroalkylene”is also meant to include mono and poly-halogenated variants.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively, and further include mono- andpoly-halogenated variants thereof. Additionally, for dialkylaminogroups, the alkyl portions can be the same or different and can also becombined to form a 3-7 membered ring with the nitrogen atom to whicheach is attached. Accordingly, a group represented as —NR^(a)R^(b) ismeant to include piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl andthe like.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“C₁₋₄ haloalkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, difluoromethyl, andthe like.

The term “aryl” means, unless otherwise stated, a polyunsaturated,typically aromatic, hydrocarbon ring, which can be a single ring ormultiple rings (up to three rings) which are fused together. The term“heteroaryl” refers to aryl ring(s) that contain from one to fiveheteroatoms selected from N, O, and S, wherein the nitrogen and sulfuratoms are optionally oxidized, and the nitrogen atom(s) are optionallyquaternized. A heteroaryl group can be attached to the remainder of themolecule through a heteroatom. Non-limiting examples of aryl groupsinclude phenyl, naphthyl and biphenyl, while non-limiting examples ofheteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimindinyl,triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl,phthalaziniyl, benzotriazinyl, purinyl, benzimidazolyl, benzopyrazolyl,benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl,benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl,imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl,quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl,imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl,pyrrolyl, thiazolyl, furyl, thienyl and the like. Optional substituentsfor each of the above noted aryl and heteroaryl ring systems can beselected from the group of acceptable substituents described furtherbelow.

The above terms (e.g., “alkyl,” “aryl” and “heteroaryl”), in someembodiments, will include both substituted and unsubstituted forms ofthe indicated radical. Preferred substituents for each type of radicalare provided below.

Substituents for the alkyl radicals (including those groups oftenreferred to as alkylene, alkenyl, alkynyl, heteroalkyl and cycloalkyl)can be a variety of groups including, but not limited to,

-halogen, —OR′, —NR′R″, —SR′, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′,—CONR′R″, —OC(O)NR′R″, —NR″C(O)R′, —NR′″C(O)NR′R″, —NR″C(O)₂R′,—NHC(NH₂)═NH, —NRC(NH₂)═NH, —NHC(NH₂)═NR′, —NR′″C(NR′R″)═N—CN,—NR′″C(NR′R″)═NOR′, —NHC(NH₂)═NR′, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″,—NR′S(O)₂R″, —NR′″S(O)₂NR′R″, —CN, —NO₂, —(CH₂)₁₋₄—OR′, —(CH₂)₁₋₄—NR′R″,—(CH₂)₁₋₄—SR′, —(CH₂)₁₋₄—SiR′R″R′″, —(CH₂)₁₋₄—OC(O)R′, —(CH₂)₁₋₄—C(O)R′,—(CH₂)₁₋₄—CO₂R′, —(CH₂)₁₋₄CONR′R″, in a number ranging from zero to (2m′+1), where m′ is the total number of carbon atoms in such radical. R′,R″ and R′″ each independently refer groups including, for example,hydrogen, unsubstituted C₁₋₆ alkyl, unsubstituted heteroalkyl,unsubstituted aryl, aryl substituted with 1-3 halogens, unsubstitutedC₁₋₆ alkyl, C₁₋₆ alkoxy or C₁₋₆ thioalkoxy groups, or unsubstitutedaryl-C₁₋₄ alkyl groups, unsubstituted heteroaryl, substitutedheteroaryl, among others. When R′ and R″ are attached to the samenitrogen atom, they can be combined with the nitrogen atom to form a 3-,4-, 5-, 6-, or 7-membered ring. For example, —NR′R″ is meant to include1-pyrrolidinyl and 4-morpholinyl. Other substitutents for alkylradicals, including heteroalkyl, alkylene, include for example, ═O,═NR′, ═N—OR′, ═N—CN, ═NH, wherein R′ include substituents as describedabove. When a substituent for the alkyl radicals (including those groupsoften referred to as alkylene, alkenyl, alkynyl, heteroalkyl andcycloalkyl) contains an alkylene linker (e.g., —(CH₂)₁₋₄—NR′R″), thealkylene linker includes halo variants as well. For example, the linker“—(CH₂)₁₋₄—” when used as part of a substituent is meant to includedifluoromethylene, 1,2-difluoroethylene, etc.

Similarly, substituents for the aryl and heteroaryl groups are variedand are generally selected from the group including, but not limited to,

-halogen, —OR′, —OC(O)R′, —NR′R″, —SR′, —R′, —CN, —NO₂, —CO₂R′,—CONR′R″, —C(O)R′, —OC(O)NR′R″, —NR″C(O)R′, —NR″C(O)₂R′, —NR′C(O)NR″R′”,—NHC(NH₂)═NH, —NR′C(NH₂)═NH, —NHC(NH₂)═NR′, —S(O)R′, —S(O)₂R′,—S(O)₂NR′R″, —NR′S(O)₂R″, —N₃, perfluoro-C₁₋₄ alkoxy, and perfluoro-C₁₋₄alkyl, —(CH₂)₁₋₄—OR′, —(CH₂)₁₋₄—NR′R″, —(CH₂)₁₋₄—SR′,—(CH₂)₁₋₄—SiR′R″R′″, —(CH₂)₁₋₄—OC(O)R′, —(CH₂)₁₋₄—C(O)R′,—(CH₂)₁₋₄—CO₂R′, —(CH₂)₁₋₄CONR′R″, in a number ranging from zero to thetotal number of open valences on the aromatic ring system; and where R′,R″ and R′″ are independently selected from hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, unsubstituted aryl andheteroaryl, (unsubstituted aryl)-C₁₋₄ alkyl, and unsubstitutedaryloxy-C₁₋₄ alkyl. Other suitable substituents include each of theabove aryl substituents attached to a ring atom by an alkylene tether offrom 1-4 carbon atoms. When a substituent for the aryl or heteroarylgroup contains an alkylene linker (e.g., —(CH₂)₁₋₄—NR′R″), the alkylenelinker includes halo variants as well. For example, the linker“—(CH₂)₁₋₄—” when used as part of a substituent is meant to includedifluoromethylene, 1,2-difluoroethylene, etc.

As used herein, the term “heteroatom” is meant to include oxygen (O),nitrogen (N), sulfur (S) and silicon (Si).

As used herein, the term “chiral” refers to molecules which have theproperty of non-superimposability of the mirror image partner, while theterm “achiral” refers to molecules which are superimposable on theirmirror image partner.

As used herein, the term “stereoisomers” refers to compounds which haveidentical chemical constitution, but differ with regard to thearrangement of the atoms or groups in space.

As used herein a wavy line “

” that intersects a bond in a chemical structure indicate the point ofattachment of the atom to which the wavy bond is connected in thechemical structure to the remainder of a molecule, or to the remainderof a fragment of a molecule.

As used herein, the representation of a group (e.g., X^(d)) inparenthesis followed by a subscript integer range (e.g., (X^(d))₀₋₂)means that the group can have the number of occurrences as designated bythe integer range. For example, (X^(d))₀₋₁ means the group X^(d) can beabsent or can occur one time.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers can separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention can contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand l or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or 1 meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer can also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which canoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

As used herein, the term “tautomer” or “tautomeric form” refers tostructural isomers of different energies which are interconvertible viaa low energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerizations. Valencetautomers include interconversions by reorganization of some of thebonding electrons.

As used herein, the term “solvate” refers to an association or complexof one or more solvent molecules and a compound of the invention.Examples of solvents that form solvates include, but are not limited to,water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid,and ethanolamine. The term “hydrate” refers to the complex where thesolvent molecule is water.

As used herein, the term “protecting group” refers to a substituent thatis commonly employed to block or protect a particular functional groupon a compound. For example, an “amino-protecting group” is a substituentattached to an amino group that blocks or protects the aminofunctionality in the compound. Suitable amino-protecting groups includeacetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ)and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a“hydroxy-protecting group” refers to a substituent of a hydroxy groupthat blocks or protects the hydroxy functionality. Suitable protectinggroups include acetyl and silyl. A “carboxy-protecting group” refers toa substituent of the carboxy group that blocks or protects the carboxyfunctionality. Common carboxy-protecting groups includephenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyland the like. For a general description of protecting groups and theiruse, see P. G. M. Wuts and T. W. Greene, Greene's Protective Groups inOrganic Synthesis 4^(th) edition, Wiley-Interscience, New York, 2006.

As used herein, the term “mammal” includes, but is not limited to,humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows,pigs, and sheep

As used herein, the term “pharmaceutically acceptable salts” is meant toinclude salts of the active compounds which are prepared with relativelynontoxic acids or bases, depending on the particular substituents foundon the compounds described herein. When compounds of the presentinvention contain relatively acidic functionalities, base addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occurring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al., “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19). Certain specific compounds of the presentinvention contain both basic and acidic functionalities that allow thecompounds to be converted into either base or acid addition salts.

The neutral forms of the compounds can be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. As used herein the term “prodrug” refers tothose compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Prodrugs of the invention include compounds wherein an amino acidresidue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues, is covalently joined through an amide orester bond to a free amino, hydroxy or carboxylic acid group of acompound of the present invention. The amino acid residues include butare not limited to the 20 naturally occurring amino acids commonlydesignated by three letter symbols and also includes phosphoserine,phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine,demosine, isodemosine, gamma-carboxyglutamate, hippuric acid,octahydroindole-2-carboxylic acid, statine,1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,ornithine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, citrulline, homocysteine, homoserine,methyl-alanine, para-benzoylphenylalanine, phenylglycine,propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.

Additional types of prodrugs are also encompassed. For instance, a freecarboxyl group of a compound of the invention can be derivatized as anamide or alkyl ester. As another example, compounds of this inventioncomprising free hydroxy groups can be derivatized as prodrugs byconverting the hydroxy group into a group such as, but not limited to, aphosphate ester, hemisuccinate, dimethylaminoacetate, orphosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. etal., (1996) Improved oral drug delivery: solubility limitations overcomeby the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamateprodrugs of hydroxy and amino groups are also included, as are carbonateprodrugs, sulfonate esters and sulfate esters of hydroxy groups.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers, wherein the acyl group can be an alkyl ester optionallysubstituted with groups including, but not limited to, ether, amine andcarboxylic acid functionalities, or where the acyl group is an aminoacid ester as described above, are also encompassed. Prodrugs of thistype are described in J. Med. Chem., (1996), 39:10. More specificexamples include replacement of the hydrogen atom of the alcohol groupwith a group such as (C₁₋₆)alkanoyloxymethyl,1-((C₁₋₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁₋₆)alkanoyloxy)ethyl,(C₁₋₆)alkoxycarbonyloxymethyl, N—(C₁₋₆)alkoxycarbonylaminomethyl,succinoyl, (C₁₋₆)alkanoyl, alpha-amino(C₁₋₄)alkanoyl, arylacyl andalpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where eachalpha-aminoacyl group is independently selected from the naturallyoccurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁₋₆)alkyl)₂ or glycosyl(the radical resulting from the removal of a hydroxyl group of thehemiacetal form of a carbohydrate).

For additional examples of prodrug derivatives, see, for example, a)Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methodsin Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985); b) A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design andApplication of Prodrugs,” by H. Bundgaard p. 113-191 (1991); c) H.Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988);and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each ofwhich is specifically incorporated herein by reference.

Additionally, the present invention provides for metabolites ofcompounds of the invention. As used herein, a “metabolite” refers to aproduct produced through metabolism in the body of a specified compoundor salt thereof. Such products can result for example from theoxidation, reduction, hydrolysis, amidation, deamidation,esterification, deesterification, enzymatic cleavage, and the like, ofthe administered compound.

Metabolite products typically are identified by preparing aradiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention,administering it parenterally in a detectable dose (e.g., greater thanabout 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, orto man, allowing sufficient time for metabolism to occur (typicallyabout 30 seconds to 30 hours) and isolating its conversion products fromthe urine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolite products, so long as they arenot otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of the compounds of the invention.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention can exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention.

The compounds of the present invention can also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the present invention alsoembraces isotopically-labeled variants of the present invention whichare identical to those recited herein, bur the for the fact that one ormore atoms are replace by an atom having the atomic mass or mass numberdifferent from the predominant atomic mass or mass number usually foundin nature for the atom. All isotopes of any particular atom or elementas specified are contemplated within the scope of the compounds of theinvention, and their uses. Exemplary isotopes that can be incorporatedin to compounds of the invention include istopes of hydrogen, carbon,nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine,such as ²H (“D”), ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P,³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I. Certain isotopically labeled compounds ofthe present invention (e.g., those labeled with ³H or ¹⁴C) are useful incompound and/or substrate tissue distribution assays. Tritiated (³H) andcarbon-14 (¹⁴C) isotopes are useful for their ease of preparation anddetectability. Further substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C, and ¹⁸Fare useful for positron emission tomography (PET) studies to examinesubstrate receptor occupancy. Isotopically labeled compounds of thepresent inventions can generally be prepared by following proceduresanalogous to those disclosed in the Schemes and/or in the Examplesherein below, by substituting an isotopically labeled reagent for anon-isotopically labeled reagent.

The terms “treat” and “treatment” refer to both therapeutic treatmentand/or prophylactic treatment or preventative measures, wherein theobject is to prevent or slow down (lessen) an undesired physiologicalchange or disorder, such as, for example, the development or spread ofcancer. For purposes of this invention, beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease or disorder, stabilized (i.e., notworsening) state of disease or disorder, delay or slowing of diseaseprogression, amelioration or palliation of the disease state ordisorder, and remission (whether partial or total), whether detectableor undetectable. “Treatment” can also mean prolonging survival ascompared to expected survival if not receiving treatment. Those in needof treatment include those already with the disease or disorder as wellas those prone to have the disease or disorder or those in which thedisease or disorder is to be prevented.

The phrase “therapeutically effective amount” means an amount of acompound of the present invention that (i) treats or prevents theparticular disease, condition, or disorder, (ii) attenuates,ameliorates, or eliminates one or more symptoms of the particulardisease, condition, or disorder, or (iii) prevents or delays the onsetof one or more symptoms of the particular disease, condition, ordisorder described herein. For cancer therapy, efficacy can, forexample, be measured by assessing the time to disease progression (TTP)and/or determining the response rate (RR). In the case of immunologicaldisease, the therapeutic effective amount is an amount sufficient todecrease or alleviate an allergic disorder, the symptoms of anautoimmune and/or inflammatory disease (e.g. psoriasis or inflammatorybowel disease), or the symptoms of an acute inflammatory reaction (e.g.asthma). In some embodiments, a therapeutically effective amount is anamount of a chemical entity described herein sufficient to significantlydecrease the activity or number of B-cells.

The term “bioavailability” refers to the systemic availability (i.e.,blood/plasma levels) of a given amount of drug administered to apatient. Bioavailability is an absolute term that indicates measurementof both the time (rate) and total amount (extent) of drug that reachesthe general circulation from an administered dosage form.

“Inflammatory disease or disorder” as used herein can refer to anydisease, disorder, or syndrome in which an excessive or unregulatedinflammatory response leads to excessive inflammatory symptoms, hosttissue damage, or loss of tissue function.

“Inflammation” as used herein refers to a localized, protective responseelicited by injury or destruction of tissues, which serves to destroy,dilute, or wall off (sequester) both the injurious agent and the injuredtissue. Inflammation is notably associated with influx of leukocytesand/or neutrophil chemotaxis. Inflammation can result from infectionwith pathogenic organisms and viruses and from noninfectious means suchas trauma or reperfusion following myocardial infarction or stroke,immune response to foreign antigen, and autoimmune responses.

The terms “cancer” and “cancerous” refer to or describe thephysiological condition in mammals that is typically characterized byunregulated cell growth and/or proliferation. A “tumor” comprises one ormore cancerous cells. Examples of cancer include, but are not limitedto, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoidmalignancies.

“Autoimmune disease” as used herein refers to any group of disorders inwhich tissue injury is associated with humoral or cell-mediatedresponses to the body's own constituents.

Compounds

The compounds of the invention have Formula I:

in which for compounds of Formula I, Y is nitrogen and the subscript bis the integer 0, or Y is carbon and the subscript b is the integer 1.R¹ is C₁₋₂ alkyl, C₁₋₂ haloalkyl or —CH₂—OH. R² is C₁₋₆ alkyl, C₁₋₆haloalkyl, 3-7 membered cycloalkyl, C₁₋₆ alkylene-3-7 memberedcycloalkyl, phenyl, 5-6 membered heteroaryl, —C(═O)R^(x2a),—C(═O)OR^(x2a) or, —C(═O)NR^(x2a)R^(x2b), in which R^(x2a) is selectedfrom the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ heteroalkyl, 3-8 membered cycloalkyl, 3-8 memberedheteroalkyl, —(C₁₋₆ alkylene)-(3-8 membered cycloalkyl), —(C₁₋₆alkylene)-(3-8 membered heterocycloalkyl), —(C₁₋₆ alkylene)-(6-memberedaryl) and —(C₁₋₆ alkylene)-(5-6 membered heteroaryl), and R^(x2b) isselected from the group consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl and C₁₋₆ heteroalkyl. In Formula I, when R^(x2a)and R^(x2b) are attached to the same nitrogen atom, then they areoptionally combined to form a 3-7 membered heterocycloalkyl furthercomprising 0-2 additional heteroatoms selected from N, O and S.Alternatively, in Formula I, R¹ and R² are combined to form a 3-8membered cycloalkyl or 3-8 membered heterocycloalkyl and optionallyfused thereto is a 5-6 membered heteroaryl ring comprising 1-3heteroatoms selected from N, O and S. The aliphatic and/or aromaticportions of R¹ and R² either independently or when combined, areoptionally substituted with 1 to 5 R^(R1/2) substitutents selected fromthe group consisting of F, Cl, Br, I, —OH, —NH₂, —SH, —CF₃, —OCF₃, —SF₅,—OCH₃, —(X^(a))₀₋₁—CN, —(X^(a))₀₋₁—NO₂, —(X^(a))₀₋₁—N₃, —(X^(a))₀₋₁—OH,—(X^(a))₀₋₁—H, —(X^(a))₀₋₁—OR^(a), —(X^(a))₀₋₁—N(H)R^(a),—(X^(a))₀₋₁—N(H)₂, —(X^(a))₀₋₁—N(R^(a))₂, —(X^(a))₀₋₁—SR^(a),—(X^(a))₀₋₁—SH, —(X^(a))₀₋₁—C(O)R^(a), —(X^(a))₀₋₁—S(O)₂R^(a),—(X^(a))₀₋₁—S(O)R^(a), —N(X^(a))₀₋₁—N(H)S(O)₂R^(a),—(X^(a))₀₋₁—N(R^(a))S(O)₂R^(a), —(X^(a))₀₋₁—OC(O)R^(a),—(X^(a))₀₋₁—N(H)C(O)OR^(a), —(X^(a))₀₋₁—N(R^(a))C(O)OR^(a),—(X^(a))₀₋₁—C(═O)OR^(a), —(X^(a))₀₋₁—C(═O)OH,—(X^(a))₀₋₁—C(═O)N(H)R^(a), —(X^(a))₀₋₁—C(═O)N(R^(a))R^(a),—(X^(a))₀₋₁—N(H)C(═O)R^(a), —(X^(a))₀₋₁—N(R^(a))C(═O)R^(a),—(X^(a))₀₋₁—N(H)C(═O)OR^(a) and —(X^(a))₀₋₁—N(R^(a))C(═O)OR^(a), inwhich X^(a) is selected from the group consisting of C₁₋₆ alkylene, C₂₋₆alkenylene, C₂₋₆ alkynylene, C₁₋₆ heteroalkylene, 3-6 memberedcycloalkylene and 3-6 membered heterocycloalkylene, and R^(a) at eachoccurrence is independently selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ heteroalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3-7membered cycloalkyl and 3-7 membered heterocycloalkyl. In Formula I, Ais selected from the group consisting of:

in which X¹, X² and X³ are independently N or CR⁵, wherein at least oneof X¹, X² and X³ is CR^(s), where R⁵ is selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, halogen, —OC₁₋₆alkyl, 3-6 membered heterocycloalkyl-C₁₋₃alkyleneoxy-, —CN, —NO₂,—NH(C₁₋₆ alkyl), —NH₂ and —N(C₁₋₆ alkyl)₂. In Formula I, R³ is 5-10membered heteroaryl optionally substituted with —NR^(x3a)R^(x3b), inwhich R^(x3a) and R^(x3b) are each independently selected from the groupconsisting of hydrogen, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₁₋₆ alkoxy, C₁₋₆ heteroalkyl, 6-10 membered aryl and 5-10membered heteroaryl. In Formula I, R³ and the R^(x3a) and R^(x3b) groupsof R³, if present, are further each independently optionally substitutedwith 1 to 5 R^(R3) substituents selected from the group consisting of F,Cl, Br, I, —OH, —NH₂, —SH, —CF₃, —OCF₃, —SF_(S), —OCH₃, —(X^(b))₀₋₁—CN,—(X^(b))₀₋₁—NO₂, —(X^(b))₀₋₁—N₃, —(X^(b))—OH, —(X^(b))—H,—(X^(b))₀₋₁—OR^(b), —(X^(b))₀₋₁—N(H)R^(b), —(X^(b))—N(H)₂,—(X^(b))₀₋₁—N(R^(b)), —(X^(b))₀₋₁—SR^(b), —(X^(b))₀₋₁—SH,—(X^(b))₀₋₁—C(O)R^(b), —(X^(b))₀₋₁—S(O)₂R^(b), —(X^(b))₀₋₁—S(O)R^(b),—(X^(b))₀₋₁—N(H)S(O)₂R^(b), —(X^(b))₀₋₁—N(R^(b))S(O)₂R^(b),—(X^(b))₀₋₁—OC(O)R^(b), —(X^(b))₀₋₁—N(H)C(O)OR^(b),—(X^(b))₀₋₁—N(R^(b))C(O)OR^(b), —(X^(b))₀₋₁—C(═O)OR^(b),—(X^(b))₀₋₁—C(═O)OH, —(X^(b))₀₋₁—C(═O)N(H)R^(b),—(X^(b))₀₋₁—C(═O)N(R^(b))R^(b), —(X^(b))₀₋₁—N(H)C(═O)R^(b),—(X^(b))₀₋₁—N(R^(b))C(═O)R^(b), —(X^(b))₀₋₁—N(H)C(═O)OR^(b) and—(X^(b))₀₋₁—N(R^(b))C(═O)OR^(b), in which X^(b) is selected from thegroup consisting of C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene,C₁₋₆ heteroalkylene, C₃₋₆ cycloalkylene and C₃₋₆ heterocycloalkylene,and R^(b) at each occurrence is independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ heteroalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 3-7 membered cycloalkyl and 3-7 memberedheterocycloalkyl. In Formula I, R⁴ is -(L)₀₋₁-R^(x4a), wherein L isselected from the group consisting of —O—, —N(H)—, —C(═O)—, C₁₋₄alkylene, C₁₋₄ haloalkylene, C₂₋₄ alkenylene, C₂₋₄ alkynylene and C₁₋₄heteroalkylene and R^(x4a) is selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl andC₁₋₆ heteroalkyl, 3-6 membered cycloalkyl, 3-9 memberedheterocycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl. Thealiphatic or aromatic portions of R⁴ are independently substituted with0 to 5 R^(R4) substituents selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ heteroalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino,C₁₋₆ dialkylamino, C₃₋₆ heterocycloalkyl, F, Cl, Br, I, —OH, —NH₂, —SH,—CF₃, —OCF₃, —SF₅, —(X^(c))₀₋₁—CN, —(X^(c))₀₋₁—NO₂, —(X^(c))₀₋₁—N₃,—(X^(c))—OH, —(X^(c))₀₋₁—OR^(c), —(X^(c))—H, —(X^(c))₀₋₁—R^(c),—(X^(c))₀₋₁—N(H)R^(c), —(X^(c))₀₋₁—N(R^(c))₂, —(X^(c))₀₋₁—SR^(c),—(X^(c))₀₋₁—C(O)R^(c), —(X^(c))₀₋₁—S(O)₂R^(c), —(X^(c))₀₋₁—S(O)R^(c),—(X^(c))₀₋₁—N(H)S(O)₂R^(c), —(X^(c))₀₋₁—N(R^(c))S(O)₂R^(c),—(X^(c))₀₋₁—C(═O)OR^(c), —(X^(c))₀₋₁—C(═O)OH,—(X^(c))₀₋₁—C(═O)N(H)R^(c), —(X^(c))₀₋₁—C(═O)N(R^(c))R^(c),—(X^(c))₀₋₁—N(H)C(═O)R^(c) and —(X^(c))₀₋₁—N(R^(c))C(═O)R^(c), in whichX^(c) is selected from the group consisting of C₁₋₆ alkylene, C₂₋₆alkenylene, C₂₋₆ alkynylene, C₁₋₆ heteroalkylene, C₃₋₆ cycloalkylene andC₃₋₆ heterocycloalkylene, and R^(c) at each occurrence is independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆heteroalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3-7 membered cycloalkyl, 3-7membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl. InFormula I, any two R^(c) groups attached to the same nitrogen atom areoptionally combined to form a 3-7 membered heterocycloalkyl or 5-10membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, Y is nitrogenand the subscript b is the integer 0, or Y is carbon and the subscript bis the integer 1. R¹ is C₁₋₂ alkyl, C₁₋₂ haloalkyl or —CH₂—OH. R² isC₁₋₆ alkyl, C₁₋₆ haloalkyl, 3-7 membered cycloalkyl, phenyl, 5-6membered heteroaryl, —C(═O)R^(x2a), —C(═O)OR^(x2a) or—C(═O)NR^(x2a)R^(x2b), in which R^(x2a) is selected from the groupconsisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆heteroalkyl, 3-8 membered cycloalkyl, 3-8 membered heteroalkyl, —(C₁₋₆alkylene)-(3-8 membered cycloalkyl), —(C₁₋₆ alkylene)-(3-8 memberedheterocycloalkyl), —(C₁₋₆ alkylene)-(6-membered aryl) and —(C₁₋₆alkylene)-(5-6 membered heteroaryl), and R^(x2b) is selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl andC₁₋₆ heteroalkyl. In Formula I, when R^(x2a) and R^(x2b) are attached tothe same nitrogen atom, then they are optionally combined to form a 3-7membered heterocycloalkyl further comprising 0-2 additional heteroatomsselected from N, O and S. Alternatively, in Formula I, R¹ and R² arecombined to form a 3-8 membered cycloalkyl or 3-8 memberedheterocycloalkyl. The aliphatic and/or aromatic portions of R¹ and R²either independently or when combined, are optionally substituted with 1to 5 R^(R1/2) substitutents selected from the group consisting of F, Cl,Br, I, —OH, —NH₂, —SH, —CF₃, —OCF₃, —SF₅, —OCH₃, —(X^(a))₀₋₁—CN,—(X^(a))₀₋₁—NO₂, —(X^(a))₀₋₁—N₃, —(X^(a))₀₋₁—OH, —(X^(a))₀₋₁—H,—(X^(a))₀₋₁—OR^(a), —(X^(a))₀₋₁—N(H)R^(a), —(X^(a))₀₋₁—N(H)₂,—(X^(a))₀₋₁—N(R^(a))₂, —(X^(a))₀₋₁—SR^(a), —(X^(a))₀₋₁—SH,—(X^(a))₀₋₁—C(O)R^(a), —(X^(a))₀₋₁—S(O)₂R^(a), —(X^(a))₀₋₁—S(O)R^(a),—(X^(a))₀₋₁—N(H)S(O)₂R^(a), —(X^(a))₀₋₁—N(R^(a))S(O)₂R^(a),—(X^(a))₀₋₁—OC(O)R^(a), —(X^(a))₀₋₁—N(H)C(O)OR^(a),—(X^(a))₀₋₁—N(R^(a))C(O)OR^(a), —(X^(a))₀₋₁—C(═O)OR^(a),—(X^(a))₀₋₁—C(═O)OH, —(X^(a))₀₋₁—C(═O)N(H)R^(a),—(X^(a))₀₋₁—C(═O)N(R^(a))R^(a), —(X^(a))₀₋₁—N(H)C(═O)R^(a),—(X^(a))₀₋₁—N(R^(a))C(═O)R^(a), —(X^(a))₀₋₁—N(H)C(═O)OR^(a) and—(X^(a))₀₋₁—N(R^(a))C(═O)OR^(a), in which X^(a) is selected from thegroup consisting of C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene,C₁₋₆ heteroalkylene, 3-6 membered cycloalkylene and 3-6 memberedheterocycloalkylene, and R^(a) at each occurrence is independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆heteroalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3-7 membered cycloalkyl and 3-7membered heterocycloalkyl. In Formula I, A is selected from the groupconsisting of:

in which X¹, X² and X³ are independently N or CR⁵, wherein at least oneof X¹, X² and X³ is CR⁵, where R⁵ is selected from the group consistingof hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, halogen, —OC₁₋₆ alkyl, 3-6membered heterocycloalkyl-C₁₋₃alkyleneoxy-, —CN, —NO₂, —NH(C₁₋₆ alkyl),—NH₂ and —N(C₁₋₆ alkyl)₂. In Formula I, R³ is 5-10 membered heteroaryloptionally substituted with —NR^(x3a)R^(x3b), in which R^(x3a) andR^(x3b) are each independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ heteroalkyl, 6-10 membered aryl and 5-10 memberedheteroaryl. In Formula I, R³ and the R^(x3a) and R^(x3b) groups of R³,if present, are further each independently optionally substituted with 1to 5 R^(R3) substituents selected from the group consisting of F, Cl,Br, I, —OH, —NH₂, —SH, —CF₃, —OCF₃, —SF₅, —OCH₃, —(X^(b))₀₋₁—CN,—(X^(b))₀₋₁—NO₂, —(X^(b))₀₋₁—N₃, —(X^(b))—OH, —(X^(b))—H,—(X^(b))₀₋₁—OR^(b), —(X^(b))₀₋₁—N(H)R^(b), —(X^(b))—N(H)₂,—(X^(b))₀₋₁—N(R^(b)), —(X^(b))₀₋₁—SR^(b), —(X^(b))₀₋₁—SH,—(X^(b))₀₋₁—C(O)R^(b), —(X^(b))₀₋₁—S(O)₂R^(b), —(X^(b))₀₋₁—S(O)R^(b),—(X^(b))₀₋₁—N(H)S(O)₂R^(b), —(X^(b))₀₋₁—N(R^(b))S(O)₂R^(b),—(X^(b))₀₋₁—OC(O)R^(b), —(X^(b))₀₋₁—N(H)C(O)OR^(b),—(X^(b))₀₋₁—N(R^(b))C(O)OR^(b), —(X^(b))₀₋₁—C(═O)OR^(b),—(X^(b))₀₋₁—C(═O)OH, —(X^(b))₀₋₁—C(═O)N(H)R^(b),—(X^(b))₀₋₁—C(═O)N(R^(b))R^(b), —(X^(b))₀₋₁—N(H)C(═O)R^(b),—(X^(b))₀₋₁—N(R^(b))C(═O)R^(b), —(X^(b))₀₋₁—N(H)C(═O)OR^(b) and—(X^(b))₀₋₁—N(R^(b))C(═O)OR^(b), in which X^(b) is selected from thegroup consisting of C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene,C₁₋₆ heteroalkylene, C₃₋₆ cycloalkylene and C₃₋₆ heterocycloalkylene,and R^(b) at each occurrence is independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ heteroalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 3-7 membered cycloalkyl and 3-7 memberedheterocycloalkyl. In Formula I, R⁴ is -(L)₀₋₁-R^(x4a), wherein L isselected from the group consisting of —O—, —N(H)—, —C(═O)—, C₁₋₄alkylene, C₁₋₄ haloalkylene, C₂₋₄ alkenylene, C₂₋₄ alkynylene and C₁₋₄heteroalkylene and R^(x4a) is selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl andC₁₋₆ heteroalkyl, 3-6 membered cycloalkyl, 3-9 memberedheterocycloalkyl, 6-10 membered aryl and 5-10 membered heteroaryl. Thealiphatic or aromatic portions of R⁴ are independently substituted with0 to 5 R^(R4) substituents selected from the group consisting of C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₆ heteroalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino,C₁₋₆ dialkylamino, C₃₋₆ heterocycloalkyl, F, Cl, Br, I, —OH, —NH₂, —SH,—CF₃, —OCF₃, —SF₅, —(X^(c))₀₋₁—CN, —(X^(c))₀₋₁—NO₂, —(X^(c))₀₋₁—N₃,—(X^(c))—OH, —(X^(c))₀₋₁—OR^(c), —(X^(c))—H, —(X^(c))₀₋₁—R^(c),—(X^(c))₀₋₁—N(H)R^(c), —(X^(c))₀₋₁—N(R^(c))₂, —(X^(c))₀₋₁—SR^(c),—(X^(c))₀₋₁—C(O)R^(c), —(X^(c))₀₋₁—S(O)₂R^(c), —(X^(c))₀₋₁—S(O)R^(c),—(X^(c))₀₋₁—N(H)S(O)₂R^(c), —(X^(c))₀₋₁—N(R^(c))S(O)₂R^(c),—(X^(c))₀₋₁—C(═O)OR^(c), —(X^(c))₀₋₁—C(═O)OH,—(X^(c))₀₋₁—C(═O)N(H)R^(c), —(X^(c))₀₋₁—C(═O)N(R^(c))R^(c),—(X^(c))₀₋₁—N(H)C(═O)R^(c) and —(X^(c))₀₋₁—N(R^(c))C(═O)R^(c), in whichX^(c) is selected from the group consisting of C₁₋₆ alkylene, C₂₋₆alkenylene, C₂₋₆ alkynylene, C₁₋₆ heteroalkylene, C₃₋₆ cycloalkylene andC₃₋₆ heterocycloalkylene, and R^(c) at each occurrence is independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆heteroalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3-7 membered cycloalkyl, 3-7membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl. InFormula I, any two R^(c) groups attached to the same nitrogen atom areoptionally combined to form a 3-7 membered heterocycloalkyl or 5-10membered heteroaryl comprising 1-3 heteroatoms selected from N, O and S.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, R³ issubstituted with —NR^(x3a)R^(x3b), in which R³ and R^(x3a) and R^(x3b)are optionally substituted with 1 to 5 R^(R3) substituents.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, Y is nitrogenand the subscript b is the integer 0.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, Y is carbon andthe subscript b is the integer 1.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, A is selectedfrom the group consisting of

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, R³ is selectedfrom the group consisting of pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, purinyl, pyrrolopyrimidinyl,triazolopyrimidinyl, pyrazolopyrimidinyl, pyrrolopyrazinyl,pyrazolopyrazinyl, triazolopyrazinyl, imidazolopyrazinyl,pyrrolopyridazinyl, pyrazoloyridazinyl, triazoloyridazinyl,imidazoloyridazinyl, furopyrimidinyl, thienopyrimidinyl,oxazolopyrimidinyl, thiazolopyrimidinyl, pyrrolyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyland thiadiazolyl, in which R³ is substituted with NR^(x3a)R^(x3b), andin which R³ and the R^(x3a) and R^(x3b) group are each independentlyfurther optionally substituted with 1 to 5 R^(R3) substituents.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, R³ is selectedfrom the group consisting of pyridyl, pyrimidinyl, pyrazinyl,pyridazinyl, triazinyl, pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl,oxadiazolyl, thiazolyl, isothiazolyl and thiadiazolyl and wherein R³ issubstituted with NR^(x3a)R^(x3b) in which R³ and the R^(x3a) and R^(x3b)group are further each independently optionally substituted with 1 to 3R^(R3) substituents.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, R^(x3a) andR^(x3b) is each independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ heteroalkyl, 6-10 membered aryl and 5-10 memberedheteroaryl, in which at least one of R^(x3a) and R^(x3b) is hydrogen.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, R^(x3a) andR^(x3b) is each independently selected from the group consisting ofhydrogen, methyl, ethyl, propyl, isopropyl, phenyl and pyridyl, and inwhich at least one of R^(x3a) and R^(x3b) is hydrogen.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, R^(x3a) andR^(x3b) are each hydrogen.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, R^(R3) isselected from the group consisting F, Cl, Br, I, —OH, —NH₂, —CF₃, —OCF₃,—OCH₃, —NO₂, —X^(b)—NO₂, —X^(b)—OH, —X^(b)—H, —X^(b)—OR^(b), —OR^(b),—X^(b)—N(H)R^(b), —N(H)R^(b), —X^(b)—N(H)₂, —X^(b)—N(R^(b)), —N(R^(b)),—C(═O)N(H)R^(b), —X^(b)—C(═O)N(H)R^(b), —C(═O)N(R^(b))R^(b),—X^(b)—C(═O)N(R^(b))R^(b), —X^(b)—N(H)C(═O)R^(b), —X^(b)—N(H)C(═O)R^(b),—X^(b)—N(R^(b))C(═O)R^(b) and —N(R^(b))C(═O)R^(b), in which X^(b) isselected from the group consisting of C₁₋₆ alkylene, C₂₋₆ alkenylene,C₂₋₆ alkynylene and C₁₋₆ heteroalkylene, and R^(b) at each occurrence isindependently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ heteroalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3-7 memberedcycloalkyl and 3-7 membered heterocycloalkyl.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, R^(R3) isselected from the group consisting of F, Cl, Br, I, —OH, —NH₂, —CF₃,—OCF₃, —OCH₃, —NO₂, —X^(b)—H, —OR^(b), —N(H)R^(b), —N(R^(b)),—C(═O)N(H)R^(b) and —C(═O)N(R^(b))R^(b).

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, R^(R3) isselected from the group consisting of F, Cl, Br, I, —OH, —NH₂, —CF₃,—OCF₃, —OCH₃, —NO₂, —C(═O)N(CH₃)₂ and 3-methyloxetan-3-yl-(C═O)N(H)—.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiments of compounds of Formula I, R⁴ is-(L)₀₋₁-R^(x4a), in which L is selected from the group consisting of O—,—N(H)—, —C(═O)—, C₁₋₆ alkylene, C₁₋₆ haloalkylene and C₁₋₆heteroalkylene, in which R^(x4a) is selected from the group consistingof hydrogen, 3-6 membered cycloalkyl, 3-9 membered heterocycloalkyl and5-6 membered heteroaryl, and in which the aliphatic and/or aromaticportions of R⁴ are independently optionally substituted with 1 to 5R^(R4) substituents.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, R⁴ is-(L)₀₋₁-R^(x4a), in which L is selected from the group consisting of O—,—N(H)—, —C(═O)—, C₁₋₆ alkylene, C₁₋₆ haloalkylene and C₁₋₆heteroalkylene, in which R^(x4a) is selected from the group consistingof hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,aziridinyl, azetanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 1,3-dioxolanyl,2-oxa-5-azabicyclo[2.2.1]heptanyl, oxetanyl, tetrahydropyranyl,tetrahydrothiopyranyl, tetrahydrofuranyl, morpholinyl, piperidinyl,piperazinyl, thiomorpholinyl and pyrrolidinyl, in which the aliphaticand/or aromatic portions of R⁴ are independently optionally substitutedwith 1 to 5 R^(R4) substituents.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, R⁴ is-(L)₀₋₁-R^(x4a), in which L is selected from the group consisting of O—,—N(H)—, —C(═O)—, C₁₋₆ alkylene, C₁₋₆ haloalkylene and C₁₋₆heteroalkylene, in which R^(x4a) is selected from the group consistingof hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,aziridinyl, oxetanyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydrofuranyl, morpholinyl, piperidinyl, piperazinyl,thiomorpholinyl and pyrrolidinyl, in which the aliphatic and/or aromaticportions of R⁴ are independently optionally substituted with 1 to 5R^(R4) substituents.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, R⁴ is selectedfrom the group consisting of hydrogen, —C(═O)N(CH₃)₂, —(CH₂)N(CH₃)₂,—(CH₂)NH(CH₃), morpholin-4-yl-(CH₂)—, cyclopropylmethyl,trifluoromethylethyl, —CH₂CH₂OCH₃, —OCH₂CH₃, methyl, ethyl,morpholin-4-yl-C(═O)—, pyrrolidin-1-yl-C(═O)—, CH₃OCH₂—, ethoxy andcyclopropyl.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, R⁴ is selectedfrom the group consisting of

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, R⁴ is selectedfrom the group consisting of

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, R¹ is C₁₋₆ alkylor C₁₋₆ haloalkyl; R² is C₁₋₆ alkyl, C₁₋₆ haloalkyl, 3-8 memberedcycloalkyl, phenyl or 5-6 membered heteroaryl; or alternatively R¹ andR² are combined to form a 3-6 membered cycloalkyl or 3-6 memberedheterocycloalkyl; and wherein the aliphatic and/or aromatic portions ofR¹ and R² either independently or when combined, are optionallysubstituted with 1 to 5 R^(R1/2) substitutents.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, R² is selectedfrom the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, cyclopropyl,cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, thiazolyl, imidazolyl,oxadiazolyl, triazolyl, tetrazolyl, oxazolyl, pyrazolyl, pyridyl,pyrimidinyl, pyrazinyl, pyrrolyl; or alternatively R² and R¹ arecombined to form 3-6 membered ring selected from the group consisting ofcyclobutyl, cyclopentyl, cyclohexyl oxetanyl, tetrahydrofuranyl andtetrahydropyanyl, azetidinyl, pyrrolidinyl, piperidinyl,6,7-dihydro-5H-pyrrolo[1,2-a]imidazole and6,7-dihydro-5H-cyclopenta[b]pyridine, wherein the aliphatic and/oraromatic portions of R¹ and R² either independently or when combined,are optionally substituted with 1 to 5 R^(R1/2) substituents.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, R² is selectedfrom the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, thiazolyl, oxadiazolyl, triazolyl, tetrazolyl,oxazolyl, pyrazolyl, pyrimidinyl, pyrazinyl and pyrrolyl; oralternatively R² and R¹ are combined to form 3-6 membered ring selectedfrom the group consisting of cyclobutyl, cyclopentyl, cyclohexyloxetanyl, tetrahydrofuranyl and tetrahydropyanyl, azetidinyl,pyrrolidinyl and piperidinyl, wherein the aliphatic and/or aromaticportions of R¹ and R² either independently or when combined, areoptionally substituted with 1 to 5 R^(R1/2) substituents.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, Formula I has asubformula selected from the group consisting of

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, Formula I has asubformula selected from the group consisting of:

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds for Formula I havingsubformula S-Ib, S-Ic, S-Id, S-Ie, S-If, S-Ig, S-Ih, S-Ii, S-Ij, S-Ik,S-Il, S-Im, S-In, S-Io, S-Ip, S-Iq or S-Ir, the carbon to which R¹ andR² are attached has the (S)— stereochemical configuration.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds for Formula I havingsubformula S-Iv, S-Iw, S-Ix, S-Iy S-Iz, S-Iaa, S-Iab, S-Iac, S-Iad,S-Iae, S-Iaf, S-Iag or SI-ah, the carbon to which R¹ and R² are attachedhas the (S)-stereochemical configuration.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds for Formula I havingsubformula S-Ib, S-Ic, S-Id, S-Ie, S-If, S-Ig, S-Ih, S-Ii, S-Ij, S-Ik,S-Il, S-Im, S-In, S-Io, S-Ip, S-Iq or S-Ir, the carbon to which R¹ andR² are attached has the (R)-stereochemical configuration.

In another embodiment, in compounds of Formula I or in certain aspectsof one or more embodiment(s) of compounds of Formula I, Y is carbon andthe subscript b is the integer 1; R¹ is C₁₋₆ alkyl, C₁₋₆ haloalkyl orCH₂—OH; R² is C₁₋₆ alkyl, C₁₋₆ haloalkyl, 3-8 membered cycloalkyl,phenyl or 5-6 membered heteroaryl; or alternatively R¹ and R² arecombined to form a 3-6 membered cycloalkyl or 3-6 memberedheterocycloalkyl; and in which the aliphatic and/or aromatic portions ofR¹ and R² either independently or when combined, are optionallysubstituted with 1 to 5 R^(R1/2) substitutents; A is selected from thegroup consisting of

in which R³ is selected from the group consisting of pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, purinyl,pyrrolopyrimidinyl, triazolopyrimidinyl, pyrazolopyrimidinyl,pyrrolopyrazinyl, pyrazolopyrazinyl, triazolopyrazinyl,imidazolopyrazinyl, pyrrolopyridazinyl, pyrazoloyridazinyl,triazoloyridazinyl, imidazoloyridazinyl, furopyrimidinyl,thienopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrrolyl,imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,isothiazolyl and thiadiazolyl, in which R³ is substituted withNR^(x3a)R^(x3b), in which R³ and the R^(x3a) and R^(x3b) group are eachindependently further optionally substituted with 1 to 5 R^(R3)substituents; R⁴ is -(L)₀₋₁-R^(x4a), in which L is selected from thegroup consisting of C(═O)—, C₁₋₆ alkylene, C₁₋₆ haloalkylene and C₁₋₆heteroalkylene, R^(x4a) is selected from the group consisting ofhydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl,oxetanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl,tetrahydromorpholinyl, piperidinyl, piperazinyl, thiomorpholinyl andpyrrolidinyl, wherein the aliphatic and/or aromatic portions of R⁴ areindependently optionally substituted with 1 to 5 R^(R4) substituents; R⁵is selected from the group consisting of hydrogen, C₁₋₄ alkyl, C₁₋₄haloalkyl, halogen, —OC₁₋₆ alkyl and 3-6 membered heterocycloalkyl-C₁₋₃alkyleneoxy.

In one embodiment, compounds of Formula I have chemical structures asselected from those presented in Table 1 and Table 1.1 below.

TABLE 1 No Structure Name T1-1

4-(1-(2-aminopyrimidin-4-yl)- 1H-indazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol T1-2

 

4-(1-(2-aminopyrimidin-4-yl)- 1H-benzo[d]imidazol-5-yl)-2-(thiazol-2-yl)but-3-yn-2-ol compound with 4-(1-(2-aminopyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl)-2- (thiazol-2-yl)but-3-yn-2-ol (1:1) T1-3

1-(2-aminopyrimidin-4-yl)- 1H-indazole-6-carbonitrile T1-4

4-(1-(2-aminopyrimidin-4-yl)- 1H-indazol-6-yl)-2- methylbut-3-yn-2-olT1-5

1-((1-(2-aminopyrimidin-4- yl)-1H-indazol-6- yl)ethynyl)cyclopentanolT1-6

4-(1-(2-amino-5- chloropyrimidin-4-yl)-1H- indazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol T1-7

4-(1-(2-aminopyrimidin-4-yl)- 1H-benzo[d]imidazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol T1-8

1-(2-amino-5-nitropyrimidin- 4-yl)-1H-indazole-6- carbonitrile T1-9

1-(2,5-diaminopyrimidin-4- yl)-1H-indazole-6-carbonitrile T1-10

4-(1-(2-aminopyrimidin-4-yl)- 1H-benzo[d]imidazol-6-yl)-2-methylbut-3-yn-2-ol T1-11

N-(2-amino-4-(6-cyano-1H- indazol-1-yl)pyrimidin-5-yl)-3-methyloxetane-3- carboxamide T1-12

4-(1-(2-aminopyrimidin-4-yl)- 2-methyl-1H- benzo[d]imidazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol T1-13

4-(1-(2-aminopyrimidin-4-yl)- 3-methyl-1H-indazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol T1-14

4-(1-(2-aminopyrimidin-4-yl)- 2-cyclopropyl-1H-benzo[d]imidazol-6-yl)-2- (thiazol-2-yl)but-3-yn-2-ol T1-15

4-(1-(2-aminopyrimidin-4-yl)- 1H-indazol-6-yl)-2-(oxazol-2-yl)but-3-yn-2-ol T1-16

N-(2-amino-4-(6-(3-hydroxy- 3-(thiazol-2-yl)but-1-ynyl)-1H-indazol-1-yl)pyrimidin-5- yl)-3-methyloxetane-3- carboxamide T1-17

4-(1-(2-aminopyrimidin-4-yl)- 2-cyclopropyl-1H-benzo[d]imidazol-6-yl)-2- methylbut-3-yn-2-ol T1-18

4-(1-(2-aminopyrimidin-4-yl)- 3-(morpholinomethyl)-1H-indazol-6-yl)-2-(thiazol-2- yl)but-3-yn-2-ol T1-19

4-(1-(2-aminopyrimidin-4-yl)- 1H-indazol-6-yl)-1,1-difluoro-2-methylbut-3-yn-2-ol T1-20

1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-methylbut-1-ynyl)-1H-benzo[d]imidazol- 2(3H)-one T1-21

1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-(thiazol-2- yl)but-1-ynyl)-1H-benzo[d]imidazol-2(3H)-one T1-22

4-(1-(2-aminopyrimidin-4-yl)- 1H-benzo[d]imidazol-6-yl)-2-(oxazol-2-yl)but-3-yn-2-ol T1-23

1-(4-(2-methoxypyridin-3- ylamino)-1,3,5-triazin-2-yl)-1H-indazole-6-carbonitrile T1-24

4-(1-(4-(2-methoxypyridin-3- ylamino)-1,3,5-triazin-2-yl)-1H-indazol-6-yl)-2- methylbut-3-yn-2-ol T1-25

4-(1-(2-aminopyrimidin-4-yl)- 3-((dimethylamino)methyl)-1H-indazol-6-yl)-2- methylbut-3-yn-2-ol T1-26

4-(1-(2-aminopyrimidin-4-yl)- 1H-benzo[d]imidazol-6-yl)-1,1-difluoro-2-methylbut-3- yn-2-ol T1-27

4-(1-(2-aminopyrimidin-4-yl)- 1H-benzo[d]imidazol-6-yl)-1,1,1-trifluoro-2-methylbut-3- yn-2-ol T1-28

4-(1-(2-aminopyrimidin-4-yl)- 1H-benzo[d]imidazol-6-yl)-2-(5-methylisoxazol-3-yl)but-3- yn-2-ol T1-29

1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-(thiazol-2-yl)but-1-ynyl)-N,N-dimethyl- 1H-indazole-3-carboxamide T1-30

1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-methylbut-1-ynyl)-N,N-dimethyl-1H- indazole-3-carboxamide T1-31

4-(1-(6-(2-methoxypyridin-3- ylamino)pyrimidin-4-yl)-1H-indazol-6-yl)-2-methylbut-3- yn-2-ol T1-32

4-(1-(2-aminopyrimidin-4-yl)- 3-((dimethylamino)methyl)-1H-indazol-6-yl)-2-(oxazol-2- yl)but-3-yn-2-ol T1-33

4-(1-(2-aminopyrimidin-4-yl)- 1H-benzo[d]imidazol-6-yl)-2-(1H-pyrazol-4-yl)but-3-yn-2- ol T1-34

4-(1-(2-aminopyrimidin-4-yl)- 1H-benzo[d]imidazol-6-yl)-2-cyclopropylbut-3-yn-2-ol T1-35

4-(1-(2-aminopyrimidin-4-yl)- 1H-indazol-6-yl)-2-(1H-pyrazol-4-yl)but-3-yn-2-ol T1-36

4-(1-(6-aminopyrimidin-4-yl)- 1H-indazol-6-yl)-2-methylbut- 3-yn-2-olT1-37

4-(1-(2-aminopyrimidin-4-yl)- 1H-benzo[d]imidazol-6-yl)-1-fluoro-2-methylbut-3-yn-2-ol T1-38

4-(1-(2-aminopyrimidin-4-yl)- 2-ethoxy-1H- benzo[d]imidazol-6-yl)-2-methylbut-3-yn-2-ol T1-39

4-(1-(2-aminopyrimidin-4-yl)- 5-fluoro-1H- benzo[d]imidazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol T1-40

4-(1-(2-aminopyrimidin-4-yl)- 5-fluoro-1H- benzo[d]imidazol-6-yl)-2-methylbut-3-yn-2-ol T1-41

4-(1-(2-aminopyrimidin-4-yl)- 1H-benzo[d]imidazol-6-yl)-2-(3-methylisoxazol-5-yl)but-3- yn-2-ol T1-42

4-(1-(2-aminopyrimidin-4-yl)- 3-methyl-1H-indazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol T1-43

1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-(oxazol-2-yl)but-1-ynyl)-N,N-dimethyl- 1H-indazole-3-carboxamide T1-44

4-(1-(2-aminopyrimidin-4-yl)- 1H-benzo[d]imidazol-6-yl)-2-(oxazol-2-yl)but-3-yn-2-ol T1-45

4-(1-(2-aminopyrimidin-4-yl)- 1H-benzo[d]imidazol-6-yl)-2-(oxazol-2-yl)but-3-yn-2-ol T1-46

(R)-1-(2-aminopyrimidin-4- yl)-6-(3-hydroxy-3-(thiazol-2-yl)but-1-ynyl)-N,N-dimethyl- 1H-indazole-3-carboxamide T1-47

(R)-1-(2-aminopyrimidin-4- yl)-6-(3-hydroxy-3-(thiazol-2-yl)but-1-ynyl)-1H- benzo[d]imidazol-2(3H)-one T1-48

4-(1-(2-aminopyrimidin-4-yl)- 3-methyl-1H-indazol-6-yl)-2-(3-methylisoxazol-5-yl)but- 3-yn-2-ol T1-49

(S)-4-(1-(2-aminopyrimidin- 4-yl)-3-methyl-1H-indazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2- ol T1-50

4-(1-(4-aminopyrimidin-2-yl)- 1H-benzo[d]imidazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol T1-51

4-(1-(2-aminopyrimidin-4-yl)- 3-methyl-1H-indazol-6-yl)-2-(4-methylthiazol-2-yl)but-3- yn-2-ol T1-52

1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-(3- methylisoxazol-5-yl)but-1-ynyl)-N,N-dimethyl-1H- indazole-3-carboxamide T1-53

4-(1-(4-amino-1,3,5-triazin-2- yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-2- (thiazol-2-yl)but-3-yn-2-ol T1-54

4-(1-(2-aminopyrimidin-4-yl)- 3-methyl-1H-indazol-6-yl)-2-(thiazol-5-yl)but-3-yn-2-ol T1-55

(R)-4-(1-(2-aminopyrimidin- 4-yl)-5-fluoro-3-methyl-1H-indazol-6-yl)-2-(thiazol-2- yl)but-3-yn-2-ol T1-56

4-(1-(2-aminopyrimidin-4-yl)- 3-methyl-1H-indazol-6-yl)-2-(5-methylthiazol-2-yl)but-3- yn-2-ol T1-57

4-(1-(2-aminopyrimidin-4-yl)- 3-methyl-1H-indazol-6-yl)-2-(5-methyl-1,2,4-oxadiazol-3- yl)but-3-yn-2-ol T1-58

4-(1-(2-aminopyrimidin-4-yl)- 3-methyl-1H-indazol-6-yl)-2-(5-methylisoxazol-3-yl)but- 3-yn-2-ol T1-59

1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-(5- methylisoxazol-3-yl)but-1-ynyl)-N,N-dimethyl-1H- indazole-3-carboxamide T1-60

4-(1-(4-amino-1,3,5-triazin-2- yl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)-2-(5- methylisoxazol-3-yl)but-3- yn-2-ol T1-61

4-(1-(2-aminopyrimidin-4-yl)- 3-methyl-1H-indazol-6-yl)-2-(4-methyl-1,2,5-oxadiazol-3- yl)but-3-yn-2-ol T1-62

4-(1-(2-aminopyrimidin-4-yl)- 3-methyl-1H-indazol-6-yl)-2-(pyrazin-2-yl)but-3-yn-2-ol T1-63

(R)-4-(1-(4-amino-1,3,5- triazin-2-yl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)- 2-(thiazol-2-yl)but-3-yn-2-ol T1-64

4-(1-(4-amino-1,3,5-triazin-2- yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-2-(5- methylisoxazol-3-yl)but-3-yn- 2-ol T1-65

(1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-(5-methylisoxazol-3-yl)but-1- ynyl)-1H-indazol-3- yl)(morpholino)methanoneT1-66

(1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-(5-methylisoxazol-3-yl)but-1- ynyl)-1H-indazol-3-yl)(pyrrolidin-1-yl)methanone T1-67

4-(1-(2-aminopyrimidin-4-yl)- 3-methyl-1H-indazol-6-yl)-2-(pyrimidin-2-yl)but-3-yn-2-ol T1-68

(R)-4-(1-(4-amino-1,3,5- triazin-2-yl)-2- (methoxymethyl)-1H-benzo[d]imidazol-6-yl)-2- (thiazol-2-yl)but-3-yn-2-ol T1-69

4-((1-(2-aminopyrimidin-4- yl)-3-methyl-1H-indazol-6-yl)ethynyl)-1-methylpiperidin- 4-ol T1-70

4-(1-(2-aminopyrimidin-4-yl)- 2-ethoxy-1H- benzo[d]imidazol-6-yl)-2-(5-methylisoxazol-3-yl)but-3-yn- 2-ol

TABLE 1.1 No. Structure Name T1.1-1

3-(2-aminopyrimidin-4-yl)-5- [(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1- ynyl]-1H-benzimidazol-2-one T1.1-2

(2R)-4-[3-(4-amino-1,3,5- triazin-2-yl)-2-methyl-benzimidazol-5-yl]-2-thiazol- 2-yl-but-3-yn-2-ol T1.1-3

4-[1-(2-aminopyrimidin-4-yl)- 3-(1-hydroxy-2-methyl-propyl)indazol-6-yl]-2-(5- methylisoxazol-3-yl)but-3-yn- 2-ol T1.1-4

(2R)-4-[1-(2-aminopyrimidin- 4-yl)-3- (hydroxymethyl)indazol-6-yl]-2-(5-methylisoxazol-3-yl)but-3- yn-2-ol T1.1-5

(2R)-4-[3-(4-amino-1,3,5- triazin-2-yl)-2-methyl-benzimidazol-5-yl]-2-(5- methylisoxazol-3-yl)but-3-yn- 2-ol T1.1-6

4-[1-(2-aminopyrimidin-4-yl)- 3-(1-cyclopropyl-1-hydroxy-ethyl)indazol-6-yl]-2- (5-methylisoxazol-3-yl)but-3- yn-2-olT1.1-7

(2R)-4-[1-(2-aminopyrimidin-4- yl)-3-(1-hydroxy-1-methyl-ethyl)indazol-6-yl]-2-(5- methyl-1,2,4-oxadiazol-3- yl)but-3-yn-2-olT1.1-8

(2R)-4-[1-(2-aminopyrimidin-4- yl)-3-(fluoromethyl)indazol-6-yl]-2-(5-methyl-1,2,4- oxadiazol-3-yl)but-3-yn-2-ol T1.1-9

(2R)-4-[1-(2-aminopyrimidin- 4-yl)-3-(1-hydroxy-1-methyl-ethyl)indazol-6-yl]-2-(5- methylisoxazol-3-yl)but-3-yn- 2-ol T1.1-10

3-(2-aminopyrimidin-4-yl)-5- [(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1- ynyl]-1-methyl-benzimidazol- 2-one T1.1-11

4-[3-(2-aminopyrimidin-4-yl)- 2-ethoxy-benzimidazol-5-yl]-2-(5-methylisoxazol-3-yl)but- 3-yn-2-ol T1.1-12

4-[1-(2-aminopyrimidin-4-yl)- 3-methyl-indazol-6-yl]-2-(1H-imidazol-4-yl)but-3-yn-2-ol T1.1-13

3-[1-(2-aminopyrimidin-4-yl)- 6-[3-hydroxy-3-(5-methylisoxazol-3-yl)but-1- ynyl]benzimidazol-2- yl]oxypropane-1,2-diolT1.1-14

[1-(2-aminopyrimidin-4-yl)- 6-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1- ynyl]indazol-3-yl]- morpholino-methanoneT1.1-15

1-(2-aminopyrimidin-4-yl)-6- [(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1- ynyl]-N-methyl-indazole-3- carboxamideT1.1-16

3-[2-[1-(2-aminopyrimidin-4- yl)-3-methyl-indazol-6-yl]ethynyl]-3-hydroxy-1- methyl-pyrrolidin-2-one T1.1-17

4-[3-(2-aminopyrimidin-4-yl)- 2-ethoxy-benzimidazol-5-yl]- 2-[5-(hydroxymethyl)isoxazol-3- yl]but-3-yn-2-ol T1.1-18

7-[2-[1-(2-aminopyrimidin- 4-yl)-3-methyl-indazol-6-yl]ethynyl]-5,6-dihydro- pyrrolo[1,2-a]imidazol-7-ol T1.1-19

4-[1-(2-aminopyrimidin-4-yl)- 3-methyl-indazol-6-yl]-2-[5-(fluoromethyl)isoxazol-3- yl]but-3-yn-2-ol T1.1-20

1-(2-aminopyrimidin-4-yl)-6- [(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1- ynyl]indazole-3-carboxamide T1.1-21

3-(2-aminopyrimidin-4-yl)-5- [3-hydroxy-3-[5- (hydroxymethyl)isoxazol-3-yl]but-1-ynyl]-1H- benzimidazol-2-one T1.1-22

3-(2-aminopyrimidin-4-yl)-5- [2-(7-hydroxy-5,6-dihydro-pyrrolo[1,2-a]imidazol-7- yl)ethynyl]-1-methyl- benzimidazol-2-oneT1.1-23

[1-(2-amino-5-chloro- pyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4- oxadiazol-3-yl)but-1- ynyl]indazol-3-yl]-(3-hydroxyazetidin-1- yl)methanone T1.1-24

[1-(2-aminopyrimidin-4-yl)- 6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3- yl)but-1-ynyl]indazol-3-yl]- (4-fluoro-1-piperidyl)methanone T1.1-25

(2R)-4-[3-(2-aminopyrimidin- 4-yl)-2-(oxetan-3-yloxy)benzimidazol-5-yl]-2- (5-methylisoxazol-3-yl)but- 3-yn-2-olT1.1-26

1-(2-aminopyrimidin-4-yl)-6- [3-hydroxy-3-[5- (hydroxymethyl)isoxazol-3-yl]but-1-ynyl]-N,N-dimethyl- indazole-3-carboxamide T1.1-27

4-[3-(2-aminopyrimidin-4-yl)- 2-(2- hydroxyethoxy)benzimidazol-5-yl]-2-(5-methylisoxazol-3- yl)but-3-yn-2-ol T1.1-28

7-[2-[3-(2-aminopyrimidin-4- yl)-2-ethoxy-benzimidazol-5-yl]ethynyl]-5,6-dihydro- pyrrolo[1,2-a]imidazol- 7-ol T1.1-29

4-[3-(2-aminopyrimidin-4-yl)- 2-(2,2,2- trifluoroethoxy)benzimidazol-5-yl]-2-(5-methylisoxazol-3- yl)but-3-yn-2-ol T1.1-30

1-(2-aminopyrimidin-4-yl)-6- [3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]- N,N-dimethyl-indazole-3- carboxamide T1.1-31

3-(2-aminopyrimidin-4-yl)-5- [(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1- ynyl]-1-methyl-benzimidazol- 2-one T1.1-32

3-(2-aminopyrimidin-4-yl)-1- (cyclopropylmethyl)-5-[3-hydroxy-3-(5-methylisoxazol- 3-yl)but-1-ynyl]benzimidazol- 2-one T1.1-33

4-[1-(2-aminopyrimidin-4-yl)- 3-methyl-indazol-6-yl]-2-[5-(hydroxymethyl)isoxazol-3- yl]but-3-yn-2-ol T1.1-34

[1-(2-aminopyrimidin-4-yl)- 6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3- yl)but-1-ynyl]indazol-3-yl]-(3-hydroxyazetidin-1- yl)methanone T1.1-35

(2R)-4-[1-(2-aminopyrimidin- 4-yl)-3-(1-fluoro-1-methyl-ethyl)indazol-6-yl]-2-(5- methyl-1,2,4-oxadiazol-3- yl)but-3-yn-2-olT1.1-36

3-[1-(2-aminopyrimidin-4-yl)- 6-[3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1- ynyl]indazol-3-yl]-1,1-difluoro-2-methyl-propan-2-ol T1.1-37

[1-(2-aminopyrimidin-4-yl)-6- [3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1- ynyl]indazol-3-yl]- morpholino-methanone T1.1-38

(2R)-4-[1-(2-aminopyrimidin- 4-yl)-3- (morpholinomethyl)indazol-6-yl]-2-(5-methylisoxazol-3- yl)but-3-yn-2-ol T1.1-39

1-(2-aminopyrimidin-4-yl)-6- [2-(7-hydroxy-5,6-dihydro-pyrrolo[1,2-a]imidazol-7- yl)ethynyl]-N,N-dimethyl-indazole-3-carboxamide T1.1-40

(2R)-4-[1-(2-aminopyrimidin- 4-yl)-3- (hydroxymethyl)indazol-6-yl]-2-(5-methyl-1,2,4- oxadiazol-3-yl)but-3-yn-2-ol T1.1-41

[1-(2-aminopyrimidin-4-yl)-6- [2-(7-hydroxy-5,6-dihydro-pyrrolo[1,2-a]imidazol-7- yl)ethynyl]indazol-3-yl]- morpholino-methanoneT1.1-42

4-[3-(2-aminopyrimidin-4-yl)- 2-tetrahydropyran-4-yloxy-benzimidazol-5-yl]-2-(5- methylisoxazol-3-yl)but-3-yn- 2-ol T1.1-43

4-[1-(2-aminopyrimidin-4-yl)- 3-[(3,3-difluoroazetidin-1-yl)methyl]indazol-6-yl]-2- pyrimidin-2-yl-but-3-yn-2-ol T1.1-44

(2R)-4-[3-(2-aminopyrimidin- 4-yl)-2-(2- methoxyethoxy)benzimidazol-5-yl]-2-(5-methylisoxazol-3- yl)but-3-yn-2-ol T1.1-45

4-[1-(2-aminopyrimidin-4-yl)- 3-methyl-indazol-6-yl]-2-(1H-1,2,4-triazol-3-yl)but-3-yn-2- ol T1.1-46

4-[3-(2-aminopyrimidin-4-yl)- 2-(2,2,2- trifluoroethoxy)benzimidazol-5-yl]-2-pyrimidin-2-yl-but-3- yn-2-ol T1.1-47

(2R)-4-[3-(2-aminopyrimidin- 4-yl)-2-(oxetan-3-yloxy)benzimidazol-5-yl]-2- (5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol T1.1-48

4-[3-(2-aminopyrimidin-4-yl)- 2-ethoxy-benzimidazoll-5-yl]-2-pyrimidin-2-yl-but-3 -yn-2- ol T1.1-49

4-[1-(2-aminopyrimidin-4-yl)- 3-(fluoromethyl)indazol-6-yl]-2-pyrimidin-2-yl-but-3-yn-2- ol T1.1-50

(2R)-4-[1-(2-amino-5-chloro- pyrimidin-4-yl)-3-(1-hydroxy-1-methyl-ethyl)indazol-6-yl]- 2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol T1.1-51

(2R)-4-[3-(2-aminopyrimidin- 4-yl)-2-(2- methoxyethoxy)benzimidazol-5-yl]-2-(5-methyl-1,2,4- oxadiazol-3-yl)but-3-yn-2-ol T1.1-52

4-[1-(2-aminopyrimidin-4-yl)- 3-methyl-indazol-6-yl]-1-fluoro-2-methyl-but-3-yn-2-ol T1.1-53

[1-(2-aminopyrimidin-4-yl)- 6-[2-(7-hydroxy-5,6-dihydro-cyclopenta[b]pyridin-7- yl)ethynyl]indazol-3-yl]- morpholino-methanoneT1.1-54

[1-(2-aminopyrimidin-4-yl)- 6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]- morpholino-methanone T1.1-55

1-[3-[1-(2-aminopyrimidin-4- yl)-6-[3-hydroxy-3-(5-methylisoxazol-3-yl)but-1- ynyl]benzimidazol-2-yl]oxyazetidin-1-yl]ethanone T1.1-56

4-[1-(2-aminopyrimidin-4-yl)- 3-(1-hydroxy-1-methyl-ethyl)indazol-6-yl]-2-(2- pyridyl)but-3-yn-2-ol T1.1-57

4-[1-(2-aminopyrimidin-4-yl)- 3-(1-hydroxy-1-methyl-ethyl)indazol-6-yl]-2- pyrimidin-2-yl-but-3-yn-2-ol T1.1-58

4-[3-(2-aminopyrimidin-4-yl)- 2-(2- methoxyethoxy)benzimidazol-5-yl]-2-pyrimidin-2-yl-but-3- yn-2-ol T1.1-59

4-[1-(2-aminopyrimidin-4-yl)- 3-(cyclopropyl-hydroxy-tetrahydropyran-4-yl- methyl)indazol-6-yl]-2-(5-methylisoxazol-3-yl)but-3-yn- 2-ol T1.1-60

4-[3-(2-aminopyrimidin-4-yl)- 2-(2- hydroxyethoxy)benzimidazol-5-yl]-2-pyrimidin-2-yl-but-3- yn-2-ol T1.1-61

4-[1-(2-aminopyrimidin-4-yl)- 3-(hydroxymethyl)indazol-6-yl]-2-pyrimidin-2-yl-but-3-yn- 2-ol T1.1-62

4-[3-(4-amino-1,3,5-triazin-2- yl)-2-methyl-benzimidazol-5-yl]-2-pyrimidin-2-yl-but-3-yn- 2-ol T1.1-63

[1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]-(2- oxa-6-azaspiro[3.3]heptan-6- yl)methanoneT1.1-64

1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)-N,N-dimethyl- indazole-3-carboxamide T1.1-65

(2R)-4-[1-(2-aminopyrimidin- 4-yl)-3-[(3,3-difluoroazetidin-1-yl)methyl]indazol-6-yl]-2- (5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol T1.1-66

[1-(2-aminopyrimidin-4-yl)- 6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]- (2-oxa-5- azabicyclo[2.2.1]heptan-5-yl)methanone T1.1-67

7-[2-[1-(2-aminopyrimidin-4- yl)-3-(1-hydroxy-1-methyl-ethyl)indazol-6-yl]ethynyl]- 5,6- dihydrocyclopenta[b]pyridin- 7-olT1.1-68

[1-(2-amino-5-chloro- pyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4- oxadiazol-3-yl)but-1-ynyl]indazol-3-yl]-(4-fluoro- 1-piperidyl)methanone T1.1-69

[1-(2-aminopyrimidin-4-yl)- 6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]- (2,6-dimethylmorpholin-4- yl)methanoneT1.1-70

4-[3-(2-aminopyrimidin-4-yl)- 2-[(2,2-dimethyl-1,3- dioxolan-4-yl)methoxy]benzimidazol- 5-yl]-2-(5-methylisoxazol-3- yl)but-3-yn-2-olT1.1-71

[1-(2-amino-5-chloro- pyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4- oxadiazol-3-yl)but-1- ynyl]indazol-3-yl]-(1-piperidyl)methanone T1.1-72

4-[3-(2-aminopyrimidin-4-yl)- 2-(oxetan-3- yloxy)benzimidazol-5-yl]-2-pyrimidin-2-yl-but-3-yn-2-ol T1.1-73

4-[1-(2-aminopyrimidin-4-yl)- 3-methyl-indazol-6-yl]-2-(1H-pyrazol-3-yl)but-3-yn-2-ol T1.1-74

[1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]-(2,6- dimethylmorpholin-4- yl)methanone T1.1-75

[1-(2-aminopyrimidin-4-yl)- 6-(4-fluoro-3-hydroxy-3-methyl-but-1-ynyl)indazol- 3-yl]-morpholino-methanone T1.1-76

4-[1-(2-aminopyrimidin-4-yl)- 3-methyl-indazol-6-yl]-2-oxazol-4-yl-but-3-yn-2-ol T1.1-78

4-[1-(2-aminopyrimidin-4-yl)- 3-(morpholinomethyl)indazol-6-yl]-2-pyrimidin-2-yl-but-3- yn-2-ol T1.1-79

4-[1-(2-aminopyrimidin-4-yl)- 3-[(cyclopentylamino)-cyclopropyl-methyl]indazol- 6-yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol T1.1-80

4-[3-(4-amino-1,3,5-triazin-2- yl)-2-methyl-benzimidazol-5-yl]-2-pyrazin-2-yl-but-3-yn-2- ol T1.1-81

3-(2-aminopyrimidin-4-yl)-1- (cyclopropylmethyl)-5-[(3R)-3-hydroxy-3-(5-methyl-1,2,4- oxadiazol-3-yl)but-1-ynyl]benzimidazol-2-one T1.1-82

1-(2-aminopyrimidin-4-yl)-6- [3-hydroxy-3-(3-methyl-1,2,4-oxadiazol-5-yl)but-1-ynyl]- N,N-dimethyl-indazole-3- carboxamide T1.1-83

[1-(2-aminopyrimidin-4-yl)-6- [3-hydroxy-3-(1-methyl-1,2,4-triazol-3-yl)but-1- ynyl]indazol-3-yl]- morpholino-methanone T1.1-84

[1-(2-aminopyrimidin-4-yl)-6- [3-hydroxy-3-[5-(methoxymethyl)isoxazol-3- yl]but-1-ynyl]indazol-3-yl]-morpholino-methanone T1.1-85

4-[1-(2-aminopyrimidin-4-yl)- 3-[(cyclopentylamino)-cyclopropyl-methyl]indazol-6- yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol T1.1-86

[1-(2-aminopyrimidin-4-yl)-6- [4-fluoro-3-(fluoromethyl)-3-hydroxy-but-1-ynyl]indazol- 3-yl]-morpholino-methanone T1.1-87

4-[1-[2-amino-5-(1- methylpyrazol-4-yl)pyrimidin-4-yl]indazol-6-yl]-2-methyl- but-3-yn-2-ol T1.1-88

[1-(2-aminopyrimidin-4-yl)-6- [(3S)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1- ynyl]indazol-3-yl]- morpholino-methanoneT1.1-89

[1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]-(4- methylpiperazin-1- yl)methanone T1.1-90

4-[1-(2-aminopyrimidin-4-yl)- 3-methyl-indazol-6-yl]-2-(1-methylimidazol-2-yl)but-3-yn- 2-ol T1.1-91

4-[1-(2-aminopyrimidin-4-yl)- 3-methyl-indazol-6-yl]-2-(5-methylpyrazin-2-yl)but-3-yn- 2-ol T1.1-92

4-[1-[2-amino-5-(1H-pyrazol- 4-yl)pyrimidin-4-yl]indazol-6-yl]-2-methyl-but-3-yn-2-ol T1.1-93

(2R)-4-[1-(2-amino-6-methyl- pyrimidin-4-yl)-3-methyl-indazol-6-yl]-2-(5-methyl- 1,2,4-oxadiazol-3-yl)but-3- yn-2-ol T1.1-94

4-[1-(2-amino-6-methyl- pyrimidin-4-yl)-3-methyl-indazol-6-yl]-2-pyrimidin-2- yl-but-3-yn-2-ol T1.1-95

4-[1-(2-aminopyrimidin-4-yl)- 3-(1-hydroxy-1-methyl-ethyl)indazol-6-yl]-2-(1- methylpyrazol-3-yl)but-3-yn- 2-ol T1.1-96

4-[3-(2-aminopyrimidin-4-yl)- 2-(oxetan-3- yloxy)benzimidazol-5-yl]-2-methyl-but-3-yn-2-ol T1.1-97

4-[3-(2-aminopyrimidin-4-yl)- 2-[1-(2- hydroxyethyl)azetidin-3-yl]oxy-benzimidazol-5-yl]-2- (5-methylisoxazol-3-yl)but-3- yn-2-olT1.1-98

4-[1-(2-aminopyrimidin-4-yl)- 3-methyl-indazol-6-yl]-2-(1H-imidazol-2-yl)but-3-yn-2-ol T1.1-99

4-[3-(4-amino-1,3,5-triazin-2- yl)-2-methyl-benzimidazol-5-yl]-1-cyclopropyl-2-methyl- but-3-yn-2-ol T1.1-100

4-[3-(4-amino-1,3,5-triazin-2- yl)-2-methyl-benzimidazol-5-yl]-2-methyl-but-3-yne-1,2- diol T1.1-101

(2R)-4-[1-[2- (methylamino)pyrimidin-4- yl]indazol-6-yl]-2-(5-methylisoxazol-3-yl)but-3- yn-2-ol T1.1-102

4-[1-(2-aminopyrimidin-4-yl)- 3-methyl-indazol-6-yl]-2- hydroxy-1-(3-hydroxyazetidin-1-yl)-2- methyl-but-3-yn-1-one T1.1-103

4-[1-(2-aminopyrimidin-4-yl)- 3-methyl-indazol-6-yl]-2-hydroxy-N,N,2-trimethyl-but- 3-ynamide T1.1-104

[1-(2-aminopyrimidin-4-yl)- 6-[3-hydroxy-3-(5-methylisoxazol-3-yl)but-1- ynyl]benzimidazol-2-yl]-pyrrolidin-1-yl-methanone T1.1-105

[1-(2-aminopyrimidin-4-yl)- 6-[3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1- ynyl]indazol-3-yl]- morpholino-methanoneT1.1-106

1-[2-[3-(4-amino-1,3,5-triazin- 2-yl)-2-methyl-benzimidazol-5-yl]ethynyl]cyclohexanol T1.1-107

[1-[2-[3-(4-amino-1,3,5-triazin- 2-yl)-2-methyl-benzimidazol-5-yl]ethynyl]cyclopentyl]meth- anol T1.1-108

4-[3-(2-aminopyrimidin-4-yl)- 2-(2- hydroxyethoxy)benzimidazol-5-yl]-2-(5-fluoro-2- pyridyl)but-3-yn-2-ol T1.1-109

3-[3-[3-(4-amino-1,3,5-triazin- 2-yl)-2-methyl-benzimidazol-5-yl]-1-hydroxy-prop-2- ynyl]cyclobutanol T1.1-110

2-[2-[3-(4-amino-1,3,5-triazin- 2-yl)-2-methyl-benzimidazol-5-yl]ethynyl]norbornan-2-ol T1.1-111

4-[3-(4-amino-1,3,5-triazin-2- yl)-2-methyl-benzimidazol-5- yl]-2-[4-(hydroxymethyl)thiazol-2- yl]but-3-yn-2-ol T1.1-112

2-[2-[3-[3-(4-amino-1,3,5- triazin-2-yl)-2-methyl- benzimidazol-5-yl]-1-hydroxy-1-methyl-prop-2- ynyl]thiazol-4-yl]acetonitrile T1.1-113

3-[2-[3-(4-amino-1,3,5-triazin- 2-yl)-2-methyl-benzimidazol-5-yl]ethynyl]-3-hydroxy- cyclobutanecarbonitrile T1.1-114

3-[2-[3-(4-amino-1,3,5-triazin- 2-yl)-2-methyl-benzimidazol-5-yl]ethynyl]tetrahydropyran- 3-ol T1.1-115

1-[2-[3-(4-amino-1,3,5-triazin- 2-yl)-2-methyl-benzimidazol-5-yl]ethynyl]-3- (hydroxymethyl)cyclobutanol T1.1-116

3-[2-[3-(4-amino-1,3,5-triazin- 2-yl)-2-methyl-benzimidazol-5-yl]ethynyl]oxetan-3-ol T1.1-117

1-(2-aminopyrimidin-4-yl)-6- [2-(7-hydroxy-5,6-dihydropyrrolo[1,2-c]imidazol- 7-yl)ethynyl]-N,N-dimethyl-indazole-3-carboxamide T1.1-118

4-[3-(4-amino-1,3,5-triazin-2- yl)-2-methyl-benzimidazol-5-yl]-2,2-dimethyl-but-3-yn-1-ol T1.1-119

4-[1-[4- (methylamino)pyrimidin-2- yl]indazol-6-yl]-2-(5-methylisoxazol-3-yl)but-3-yn- 2-ol T1.1-120

1-[2-[1-(2-aminopyrimidin-4- yl)-4-fluoro-indazol-6-yl]ethynyl]cyclopentanol T1.1-121

[1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-pyrimidin-4-yl-but-1-ynyl)indazol-3-yl]- morpholino-methanone T1.1-122

(2R)-4-[3-(2-aminopyrimidin- 4-yl)-2-(2- fluoroethoxy)benzimidazol-5-yl]-2-(5-methyl-1,2,4- oxadiazol-3-yl)but-3-yn-2-ol T1.1-123

4-[3-(2-aminopyrimidin-4-yl)- 2-(2- hydroxyethoxy)benzimidazol-5-yl]-2-(5-chloro-2- pyridyl)but-3-yn-2-ol T1.1-124

4-[3-(2-aminopyrimidin-4-yl)- 2-(2- fluoroethoxy)benzimidazol-5-yl]-2-pyrimidin-2-yl-but-3- yn-2-ol T1.1-125

4-[1-(2-aminopyrimidin-4-yl)- 3-methyl-indazol-6-yl]-2-thiazol-2-yl-but-3-yn-2-ol T1.1-126

4-[3-(4-amino-1,3,5-triazin-2- yl)-2-methyl-benzimidazol-5-yl]-2-methyl-1-pyrazol-1-yl- but-3-yn-2-ol T1.1-127

(2R)-4-[3-(2-aminopyrimidin- 4-yl)-2-(2-methoxy-ethylamino)benzimidazol-5- yl]-2-(5-methylisoxazol-3- yl)but-3-yn-2-olT1.1-128

7-[2-[1-(2-aminopyrimidin-4- yl)-3-methyl-indazol-6- yl]ethynyl]-5,6-dihydropyrrolo[1,2-a]imidazol- 7-ol T1.1-129

4-[1-(2-aminopyrimidin-4-yl)- 3-methyl-indazol-6-yl]-2-[1-(2-trimethylsilylethoxymeth- yl)imidazol-2-yl]but-3-yn-2-ol T1.1-130

[1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]- morpholino-methanone T1.1-131

4-[3-(2-aminopyrimidin-4-yl)- 2-(2-methoxy- ethylamino)benzimidazol-5-yl]-2-(4-methylthiazol-2- yl)but-3-yn-2-ol T1.1-132

[1-(2-aminopyrimidin-4-yl)-6- [2-(7-hydroxy-5,6-dihydrocyclopenta[b]pyridin- 7-yl)ethynyl]indazol-3-yl]-morpholino-methanone T1.1-133

4-[3-(2-aminopyrimidin-4-yl)- 2-(2- hydroxyethoxy)benzimidazol-5-yl]-2-(5-chloro-2-pyridyl)but-3- yn-2-ol T1.1-134

1-(2-aminopyrimidin-4-yl)-N- (cyanomethyl)-6-(3-hydroxy-3-pyrimidin-2-yl-but-1- ynyl)indazole-3-carboxamide T1.1-135

[1-(2-aminopyrimidin-4-yl)-6- [2-(7-hydroxy-5,6-dihydrocyclopenta[b]pyridin- 7-yl)ethynyl]indazol-3-yl]-morpholino-methanone T1.1-136

3-[2-[1-(2-aminopyrimidin-4- yl)-3-methyl-indazol-6-yl]ethynyl]-3-hydroxy-1- methyl-piperidin-2-one T1.1-137

[1-(2-aminopyrimidin-4-yl)-6- [3-hydroxy-3-(5-methyl-1,3,4-oxadiazol-2-yl)but-1- ynyl]indazol-3-yl]- morpholino-methanone T1.1-138

1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)-N-(2- methoxyethyl)-N-methyl- indazole-3-carboxamideT1.1-139

[1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]-(3,3- difluoroazetidin-1- yl)methanone T1.1-140

[1-(2-aminopyrimidin-4-yl)- 6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]-(3- azabicyclo[3.1.0]hexan-3- yl)methanoneT1.1-141

[1-(2-aminopyrimidin-4-yl)- 6-[2-(7-hydroxy-5,6-dihydrocyclopenta[b]pyridin- 7-yl)ethynyl]indazol-3-yl]-morpholino-methanone T1.1-142

1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)-N-methyl-N-(2- pyridyl)indazole-3-carboxamide T1.1-143

1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)-N-(3- pyridyl)indazole-3-carboxamide T1.1-144

[1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-oxazol-2-yl-but-1-ynyl)indazol-3-yl]- morpholino-methanone T1.1-145

[1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]-(3- hydroxy-1-piperidyl)methanone T1.1-146

[1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]-(3- hydroxyazetidin-1- yl)methanone T1.1-147

1-[1-(2-aminopyrimidin-4-yl)- 6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazole-3- carbonyl]azetidine-3- carbonitrile T1.1-148

1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)-N-(oxetan-3- yl)indazole-3-carboxamide T1.1-149

[1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]- morpholino-methanone T1.1-150

[1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]- morpholino-methanone T1.1-151

[1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-oxazol-2-yl-but-1-ynyl)indazol-3-yl]-(3- hydroxyazetidin-1- yl)methanone T1.1-152

7-[2-[3-(2-aminopyrimidin-4- yl)-2-ethoxy-benzimidazol-5-yl]ethynyl]-5,6- dihydrocyclopenta[b]pyridin- 7-ol

In another embodiment, the invention provides for compound intermediatesuseful in the synthesis of compounds of Formula I.

Synthesis of Compounds

For illustrative purposes, Schemes 1-3 show general methods forpreparing the compounds of the present invention as well as keyintermediates. For a more detailed description of the individualreaction steps, see the Examples section below. Those skilled in the artwill appreciate that other synthetic routes may be used to synthesizethe inventive compounds. Although specific starting materials andreagents are depicted in the Schemes and discussed below, other startingmaterials and reagents can be easily substituted to provide a variety ofderivatives and/or reaction conditions. In addition, many of thecompounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

In preparing compounds of Formulas I, protection of remote functionality(e.g., primary or secondary amine) of intermediates may be necessary.The need for such protection will vary depending on the nature of theremote functionality and the conditions of the preparation methods.Suitable amino-protecting groups include acetyl, trifluoroacetyl,t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and9-fluorenylmethylenoxycarbonyl (Fmoc). The need for such protection isreadily determined by one skilled in the art. For a general descriptionof protecting groups and their use, see T. W. Greene, Protective Groupsin Organic Synthesis, John Wiley & Sons, New York, 1991.

Compounds of the invention of Formula I can be synthesized according tothe Schemes presented below, in which, “R” at each occuranceindependently represents a non-interfering substituent and LG representsa leaving group, (e.g., Cl, OTs, etc.)

Step 1: Benzopyrazole (i) and heteroarene (ii) are combined underappropriate nucleophilic substitution conditions (e.g., with amine base,aprotic solvent), to form N-heteroarylated benzopyrazole (iii) (see, J.A. Zoltewicz Top. Curr. Chem. 59 (1975), p. 33). Step 2: Compound iiiwas combined with alkynyl alcohol (iv) under suitable Sonogashira typepalladium mediated coupling conditions (see, Chincilla, C., Najera, C.Chem. Rev. 2007, 107, 874-922) to form compounds of the invention, e.g.,compound v.

Step 1: Nitroaniline (vi) and heteroarene (ii) are combined underappropriate nucleophilic substitution conditions (e.g., with amine base,aprotic solvent), to form N-heteroarylated nitroaniline (vii). Step 2:Reduction of the nitro functional group of compound vii, preferablyunder conditions which avoids dehalogenation on aryl ring, producesaminoaniline (viii). Step 3: Treatment of amino-aniline (viii) withtriphogene produces benzoimidazolone compound ix. Step 4: Sonogashiratype coupling of compound ix with alkynyl alcohol iv producesbenzimidazolone compounds of the invention, e.g., compound x.

Step 1. Aminoanline (viii) can be treated with orthoformate to providebenzimidazole compound xi. Step 2: Sonogashira coupling of compound xiwith alkynyl alcohol iv, will product benzimidazole compounds of theinvention, e.g., compound xii.

Further synthetic detail and additional synthetic procedures aredescribed in the Examples section below.

Pharmaceutical Compositions and Administration

In addition to one or more of the compounds provided above (orstereoisomers, geometric isomers, tautomers, solvates, metabolites,isotopes, pharmaceutically acceptable salts, or prodrugs thereof), theinvention also provides for compositions and medicaments comprising acompound of Formula I and at least one pharmaceutically acceptablecarrier, diluent or excipient. The compositions of the invention can beused inhibiting NF-kB signaling activity in mammals (e.g, humanpatients), by for example, inhibiting NIK activity

The term “composition,” as used herein, is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

In one embodiment, the invention provides for pharmaceuticalcompositions (or medicaments) comprising a compound of Formula I (orstereoisomers, geometric isomers, tautomers, solvates, metabolites,isotopes, pharmaceutically acceptable salts, or prodrugs thereof) and apharmaceutically acceptable carrier, diluent or excipient. In anotherembodiment, the invention provides for preparing compositions (ormedicaments) comprising compounds of the invention. In anotherembodiment, the invention provides for administering compounds ofFormula I and compositions comprising compounds of Formula Ito a mammal(e.g., a human patient) in need thereof.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners. The effective amount of the compound tobe administered will be governed by such considerations, and is theminimum amount necessary to inhibit NIK activity as required to preventor treat the undesired disease or disorder, such as for example,neurodegeneration, amyloidosis, formation of neurofibrillary tangles, orundesired cell growth (e.g., cancer cell growth). For example, suchamount may be below the amount that is toxic to normal cells, or themammal as a whole.

In one example, the therapeutically effective amount of the compound ofthe invention administered parenterally per dose will be in the range ofabout 0.01-100 mg/kg, alternatively about e.g., 0.1 to 20 mg/kg ofpatient body weight per day, with the typical initial range of compoundused being 0.3 to 15 mg/kg/day. The daily does is, in certainembodiments, given as a single daily dose or in divided doses two to sixtimes a day, or in sustained release form. In the case of a 70 kg adulthuman, the total daily dose will generally be from about 7 mg to about1,400 mg. This dosage regimen may be adjusted to provide the optimaltherapeutic response. The compounds may be administered on a regimen of1 to 4 times per day, preferably once or twice per day.

The compounds of the present invention may be administered in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, etc. Such compositions may contain componentsconventional in pharmaceutical preparations, e.g., diluents, carriers,pH modifiers, sweeteners, bulking agents, and further active agents.

The compounds of the invention may be administered by any suitablemeans, including oral, topical (including buccal and sublingual),rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal and epidural and intranasal,and, if desired for local treatment, intralesional administration.Parenteral infusions include intramuscular, intravenous, intraarterial,intraperitoneal, or subcutaneous administration.

The compositions comprising compounds of Formula I are normallyformulated in accordance with standard pharmaceutical practice as apharmaceutical composition. A typical formulation is prepared by mixinga compound of the present invention and a diluent, carrier or excipient.Suitable diluents, carriers and excipients are well known to thoseskilled in the art and are described in detail in, e.g., Ansel, HowardC., et al., Ansel's Pharmaceutical Dosage Forms and Drug DeliverySystems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro,Alfonso R., et al. Remington: The Science and Practice of Pharmacy.Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C.Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press,2005. The formulations may also include one or more buffers, stabilizingagents, surfactants, wetting agents, lubricating agents, emulsifiers,suspending agents, preservatives, antioxidants, opaquing agents,glidants, processing aids, colorants, sweeteners, perfuming agents,flavoring agents, diluents and other known additives to provide anelegant presentation of the drug (i.e., a compound of the presentinvention or pharmaceutical composition thereof) or aid in themanufacturing of the pharmaceutical product (i.e., medicament).

Suitable carriers, diluents and excipients are well known to thoseskilled in the art and include materials such as carbohydrates, waxes,water soluble and/or swellable polymers, hydrophilic or hydrophobicmaterials, gelatin, oils, solvents, water and the like. The particularcarrier, diluent or excipient used will depend upon the means andpurpose for which a compound of the present invention is being applied.Solvents are generally selected based on solvents recognized by personsskilled in the art as safe (GRAS) to be administered to a mammal. Ingeneral, safe solvents are non-toxic aqueous solvents such as water andother non-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. Theformulations can also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

Acceptable diluents, carriers, excipients and stabilizers are nontoxicto recipients at the dosages and concentrations employed, and includebuffers such as phosphate, citrate and other organic acids; antioxidantsincluding ascorbic acid and methionine; preservatives (such asoctadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionicsurfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Aactive pharmaceutical ingredient of the invention (e.g., compound ofFormula I) can also be entrapped in microcapsules prepared, for example,by coacervation techniques or by interfacial polymerization, forexample, hydroxymethylcellulose or gelatin-microcapsules andpoly-(methylmethacylate) microcapsules, respectively, in colloidal drugdelivery systems (for example, liposomes, albumin microspheres,microemulsions, nano-particles and nanocapsules) or in macroemulsions.Such techniques are disclosed in Remington: The Science and Practice ofPharmacy: Remington the Science and Practice of Pharmacy (2005) 21^(st)Edition, Lippincott Williams & Wilkins, Philidelphia, Pa.

Sustained-release preparations of a compound of the invention (e.g.,compound of Formula I) can be prepared. Suitable examples ofsustained-release preparations include semipermeable matrices of solidhydrophobic polymers containing a compound of Formula I, which matricesare in the form of shaped articles, e.g., films, or microcapsules.Examples of sustained-release matrices include polyesters, hydrogels(for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers ofL-glutamic acid and gamma-ethyl-L-glutamate, non-degradableethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymerssuch as the LUPRON DEPOT™ (injectable microspheres composed of lacticacid-glycolic acid copolymer and leuprolide acetate) andpoly-D-(−)-3-hydroxybutyric acid.

The formulations include those suitable for the administration routesdetailed herein. The formulations can conveniently be presented in unitdosage form and can be prepared by any of the methods well known in theart of pharmacy. Techniques and formulations generally are found inRemington: The Science and Practice of Pharmacy: Remington the Scienceand Practice of Pharmacy (2005) 21^(st) Edition, Lippincott Williams &Wilkins, Philidelphia, Pa. Such methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more accessory ingredients.

In general the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers,diluents or excipients or finely divided solid carriers, diluents orexcipients, or both, and then, if necessary, shaping the product. Atypical formulation is prepared by mixing a compound of the presentinvention and a carrier, diluent or excipient. The formulations can beprepared using conventional dissolution and mixing procedures. Forexample, the bulk drug substance (i.e., compound of the presentinvention or stabilized form of the compound (e.g., complex with acyclodextrin derivative or other known complexation agent) is dissolvedin a suitable solvent in the presence of one or more of the excipientsdescribed above. A compound of the present invention is typicallyformulated into pharmaceutical dosage forms to provide an easilycontrollable dosage of the drug and to enable patient compliance withthe prescribed regimen.

In one example, compounds of Formula I may be formulated by mixing atambient temperature at the appropriate pH, and at the desired degree ofpurity, with physiologically acceptable carriers, i.e., carriers thatare non-toxic to recipients at the dosages and concentrations employedinto a galenical administration form. The pH of the formulation dependsmainly on the particular use and the concentration of compound, butpreferably ranges anywhere from about 3 to about 8. In one example, acompound of Formula I is formulated in an acetate buffer, at pH 5. Inanother embodiment, the compounds of Formula I are sterile. The compoundmay be stored, for example, as a solid or amorphous composition, as alyophilized formulation or as an aqueous solution.

Formulations of a compound of the invention (e.g., compound of FormulaI) suitable for oral administration can be prepared as discrete unitssuch as pills, capsules, cachets or tablets each containing apredetermined amount of a compound of the invention.

Compressed tablets can be prepared by compressing in a suitable machinethe active ingredient in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets can bemade by molding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent. The tablets canoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the active ingredient therefrom.

Tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, e.g., gelatincapsules, syrups or elixirs can be prepared for oral use. Formulationsof a compound of the invention (e.g., compound of Formula I) intendedfor oral use can be prepared according to any method known to the artfor the manufacture of pharmaceutical compositions and such compositionscan contain one or more agents including sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide apalatable preparation. Tablets containing the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipient which aresuitable for manufacture of tablets are acceptable. These excipients canbe, for example, inert diluents, such as calcium or sodium carbonate,lactose, calcium or sodium phosphate; granulating and disintegratingagents, such as maize starch, or alginic acid; binding agents, such asstarch, gelatin or acacia; and lubricating agents, such as magnesiumstearate, stearic acid or talc. Tablets can be uncoated or can be coatedby known techniques including microencapsulation to delay disintegrationand adsorption in the gastrointestinal tract and thereby provide asustained action over a longer period. For example, a time delaymaterial such as glyceryl monostearate or glyceryl distearate alone orwith a wax can be employed.

An example of a suitable oral administration form is a tablet containingabout 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250mg, 300 mg and 500 mg of the compound of the invention compounded withabout 90-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose,about 5-30 mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mgmagnesium stearate. The powdered ingredients are first mixed togetherand then mixed with a solution of the PVP. The resulting composition canbe dried, granulated, mixed with the magnesium stearate and compressedto tablet form using conventional equipment. An example of an aerosolformulation can be prepared by dissolving the compound, for example5-400 mg, of the invention in a suitable buffer solution, e.g. aphosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride,if desired. The solution may be filtered, e.g., using a 0.2 micronfilter, to remove impurities and contaminants.

For treatment of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w. When formulated in an ointment, the active ingredientcan be employed with either a paraffinic or a water-miscible ointmentbase. Alternatively, the active ingredients can be formulated in a creamwith an oil-in-water cream base.

If desired, the aqueous phase of the cream base can include a polyhydricalcohol, i.e., an alcohol having two or more hydroxyl groups such aspropylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol andpolyethylene glycol (including PEG 400) and mixtures thereof. Thetopical formulations can desirably include a compound which enhancesabsorption or penetration of the active ingredient through the skin orother affected areas. Examples of such dermal penetration enhancersinclude dimethyl sulfoxide and related analogs.

The oily phase of the emulsions of this invention can be constitutedfrom known ingredients in a known manner. While the phase can comprisemerely an emulsifier, it desirably comprises a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

Aqueous suspensions of a compound of the invention (e.g., compound ofFormula I) contain the active materials in admixture with excipientssuitable for the manufacture of aqueous suspensions. Such excipientsinclude a suspending agent, such as sodium carboxymethylcellulose,croscarmellose, povidone, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanthand gum acacia, and dispersing or wetting agents such as a naturallyoccurring phosphatide (e.g., lecithin), a condensation product of analkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), acondensation product of ethylene oxide with a long chain aliphaticalcohol (e.g., heptadecaethyleneoxycetanol), a condensation product ofethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Theaqueous suspension can also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such as sucroseor saccharin.

Formulations of a compound of the invention (e.g., compound of FormulaI) can be in the form of a sterile injectable preparation, such as asterile injectable aqueous or oleaginous suspension. This suspension canbe formulated according to the known art using those suitable dispersingor wetting agents and suspending agents which have been mentioned above.The sterile injectable preparation can also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, such as a solution in 1,3-butanediol or prepared as alyophilized powder. Among the acceptable vehicles and solvents that canbe employed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile fixed oils can conventionally be employedas a solvent or suspending medium. For this purpose any bland fixed oilcan be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid can likewise be used in the preparationof injectables.

The amount of active ingredient that can be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans cancontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which can varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion can contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which can contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which can include suspending agents and thickeningagents.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of about 0.5 to 20% w/w, for exampleabout 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration can be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration can beprepared according to conventional methods and can be delivered withother therapeutic agents such as compounds heretofore used in thetreatment of disorders as described below.

Formulations suitable for vaginal administration can be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

The formulations can be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and can be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

Indications and Methods of Treatment

The compounds of Formula I inhibit the activity of NIK. Accordingly, inanother aspect of the invention the compounds of the invention (e.g.,compounds of Formula I, or stereoisomers, geometric isomers, tautomers,solvates, metabolites, isotopes, pharmaceutically acceptable salts, orprodrugs thereof) can be used for the treatment of diseases anddisorders in a mammal, for example a human patient, I which theinhibition of NIK in the patient would be therapeutically effective. Forexample, the compounds of the invention are useful for the treatment ofdiseases or disorders in a mammal (e.g., human patient) associated withoveractive or undesired NF-kB signaling through, for example, theoveractivation of NIK. In another embodiment, the compounds of theinvention (e.g., compounds of Formula I, or stereoisomers, geometricisomers, tautomers, solvates, metabolites, isotopes, pharmaceuticallyacceptable salts, or prodrugs thereof) are used to inhibit the activityof NIK, for example in an in vitro assay setting, by contacting saidcompound of Formula I with NIK. For example, compounds of Formula I canbe used as a control compound in an in vitro assay setting. In anotherembodiment, the compounds of the invention (e.g., compounds of FormulaI, or stereoisomers, geometric isomers, tautomers, solvates,metabolites, isotopes, pharmaceutically acceptable salts, or prodrugsthereof) are used to inhibit the undesired signaling of NF-kB, e.g. inan cell proliferation assay, by introducing into a cell a compound ofFormula I. In another embodiment, the present invention provides thetreatment of diseases or disorders in a mammal (e.g., human patient)associated with overactive or undesired NF-kB signaling (e.g., cancer,inflammatory diseases, among others) said method comprisingadministering to a mammal (e.g., human patient) in need thereof atherapeutically effective amount of a compound of the invention (e.g.,compounds of Formula I, or stereoisomers, geometric isomers, tautomers,solvates, metabolites, isotopes, pharmaceutically acceptable salts, orprodrugs thereof).

Diseases and disorders treatable according to the methods of thisinvention include, cancer, inflammatory diseases autoimmune disease andproliferation induced after medical procedures (e.g., arthritis, graftrejection, inflammatory bowel disease, cell proliferation induced aftersurgery angioplasty, among others). In one embodiment, a mammal (e.g., ahuman patient) is treated with a compound of the invention (e.g.,compounds of Formula I, or stereoisomers, geometric isomers, tautomers,solvates, metabolites, isotopes, pharmaceutically acceptable salts, orprodrugs thereof) and a pharmaceutically acceptable carrier, adjuvant,or vehicle, wherein said compound of the invention (e.g., compounds ofFormula I, or stereoisomers, geometric isomers, tautomers, solvates,metabolites, isotopes, pharmaceutically acceptable salts, or prodrugsthereof) is present in an amount to inhibit NF-kB signaling through, forexample but not limited to, inhibition of NIK.

In one embodiment, a compound of the invention (e.g., compound ofFormula I, or stereoisomers, geometric isomers, tautomers, solvates,metabolites, isotopes, pharmaceutically acceptable salts, or prodrugsthereof) can be used in the treatment of cell proliferative disorders,including cancers of the following categories: (1) Cardiac: sarcoma(angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma,rhabdomyoma, fibroma, lipoma and teratoma; (2) Lung: bronchogeniccarcinoma (squamous cell, undifferentiated small cell, undifferentiatedlarge cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchialadenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma,non-small cell lung, small cell lung; (3) Gastrointestinal: esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma); (4) Genitourinary tract: kidney (adenocarcinoma,Wilm's tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma); (5) Liver: hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, hemangioma; (6) Bone: osteogenic sarcoma (osteosarcoma),fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing'ssarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma,malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginousexostoses), benign chondroma, chondroblastoma, chondromyxofibroma,osteoid osteoma and giant cell tumors; (7) Nervous system: skull(osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastomamultiform. oligodendroglioma, schwannoma, retinoblastoma, congenitaltumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); (8)Gynecological: uterus (endometrial carcinoma), cervix (cervicalcarcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma[serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); (9)Hematologic: blood (myeloid leukemia [acute and chronic], acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, myelodysplastic syndrome), Hodgkin'sdisease, non-Hodgkin's lymphoma [malignant lymphoma]; (10) Skin:advanced melanoma, malignant melanoma, basal cell carcinoma, squamouscell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma,angioma, dermatofibroma, keloids, psoriasis; (11) Adrenal glands:neuroblastoma; (12) Breast: metastatic breast; breast adenocarcinoma;(13) Colon; (14) Oral cavity; (15) Hairy cell leukemia; (16) Head andneck; (17) and others including refractory metastatic disease; Kaposi'ssarcoma; Bannayan-Zonana syndrome; and Cowden disease orLhermitte-Duclos disease, among other kinds of cancers.

In one embodiment of the invention, cancers that may be treated by thecompounds of Formula I (or stereoisomer, geometric isomer, tautomer,solvate, metabolite, pharmaceutically acceptable salt, or prodrugthereof), selected from the group consisting of Lung (brochogeniccarcinoma (non-small cell lung); Gatrointestinal—rectal, colorectal andcolon; Genitourinary tract—kidney (papillary renal cell carcinoma); andskin—head and neck squamous cell carcinoma.

In one embodiment, compound of Formula I (or stereoisomer, geometricisomer, tautomer, solvate, metabolite, pharmaceutically acceptable salt,or prodrug thereof), can be use for the treatment of a cancer selectedfrom the group consisting of head and neck squamous cell carcinomas,histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer,non-small cell lung cancer, pancreatic cancer, papillary renal cellcarcinoma, liver cancer, gastric cancers, colon cancer, leukemias,lymphomas, multiple myeloma, glioblastomas and breast carcinoma.

In one embodiment, compound of Formula I (or stereoisomer, geometricisomer, tautomer, solvate, metabolite, pharmaceutically acceptable salt,or prodrug thereof), can be used for the treatment of a cancer selectedfrom the group consisting of histiocytic lymphoma, lung adenocarcinoma,small cell lung cancer, pancreatic cancer, liver cancer, gastric cancer,colon cancer, leukemias, lymphomas, multiple myeloma, glioblastomas andbreast carcinoma.

In one embodiment, compound of Formula I (or stereoisomer, geometricisomer, tautomer, solvate, metabolite, pharmaceutically acceptable salt,or prodrug thereof), can be used for the treatment of a cancer selectedfrom the group consisting of histiocytic lymphoma, lung adenocarcinoma,small cell lung cancers, pancreatic cancer, liver cancer gastric cancer,colon cancer, leukemias, lymphomas, multiple myeloma, glioblastomas andbreast carcinoma.

In one embodiment, compound of Formula I (or stereoisomer, geometricisomer, tautomer, solvate, metabolite, pharmaceutically acceptable salt,or prodrug thereof), can be used for the treatment of cancer selectedfrom the group consisting of lymphomas, leukemias and multiple myeloma.

In one embodiment, the invention provide for the use of a compound ofFormula I (or stereoisomers, geometric isomers, tautomers, solvates,metabolites, isotopes, pharmaceutically acceptable salts, or prodrugsthereof) for the treatment of lymphoma, leukemia or multiple myeloma.

In one embodiment, the invention provides for the preparation of amedicament comprising a compound of Formula I (or stereoisomers,geometric isomers, tautomers, solvates, metabolites, isotopes,pharmaceutically acceptable salts, or prodrugs thereof) for thetreatment of lymphoma, leukemia or multiple myeloma.

In one embodiment, the invention provides for the treatment of lymphoma,leukemia or multiple myeloma, which method comprises administering aneffective amount of a compound of Formula I (or stereoisomers, geometricisomers, tautomers, solvates, metabolites, isotopes, pharmaceuticallyacceptable salts, or prodrugs thereof).

In one embodiment, compound of the invention (e.g., compounds of FormulaI, or stereoisomers, geometric isomers, tautomers, solvates,metabolites, isotopes, pharmaceutically acceptable salts, or prodrugsthereof) are useful for the treatment of inflammatory diseases andconditions including, but not limited to, asthma, lupus, COPD, rhinitis,multiple sclerosis, IBD, arthritis, gastritis, rheumatoid arthritis,dermatitis, endometriosis, transplant rejection, cardiac infarction,Alzheimer's diseases, diabetes Type II, inflammatory bowel disease,sepsis, and artherosclerosis.

In one embodiment, compound of the invention (e.g., compounds of FormulaI, or stereoisomers, geometric isomers, tautomers, solvates,metabolites, isotopes, pharmaceutically acceptable salts, or prodrugsthereof) are useful for the treatment of inflammatory diseases andconditions including, but not limited to, lupus, COPD and rheumatoidarthritis.

In one embodiment, the invention provides for the use of a compound ofFormula I (or stereoisomers, geometric isomers, tautomers, solvates,metabolites, isotopes, pharmaceutically acceptable salts, or prodrugsthereof) for the treatment of an inflammatory condition.

In one embodiment, the invention provideds for the use of a compound ofFormula I (or stereoisomers, geometric isomers, tautomers, solvates,metabolites, isotopes, pharmaceutically acceptable salts, or prodrugsthereof) for the preparation of a medicament for the treatment of aninflammatory condition.

In one embodiment, the invention provides for a compound of Formula I(or stereoisomers, geometric isomers, tautomers, solvates, metabolites,isotopes, pharmaceutically acceptable salts, or prodrugs thereof) forthe treatment of an inflammatory condition.

In one embodiment, the invention provides for a method for the treatmentof an inflammatory condition, which method comprises administering aneffective amount of a compound of Formula I (or stereoisomers, geometricisomers, tautomers, solvates, metabolites, isotopes, pharmaceuticallyacceptable salts, or prodrugs thereof).

In one embodiment, the invention provides for the treatment of aninflammatory condition selected from the group consisting of asthma,lupus, COPD, rhinitis, multiple sclerosis, IBD, arthritis, rheumatoidarthritis, dermatisis, endometriosis and transplant rejection, whichmethod comprises administering an effective amount of a compound ofFormula I (or stereoisomers, geometric isomers, tautomers, solvates,metabolites, isotopes, pharmaceutically acceptable salts, or prodrugsthereof).

Combinations

The compounds of Formula I (or stereoisomer, geometric isomer, tautomer,solvate, metabolite, pharmaceutically acceptable salt, or prodrugthereof) may be employed alone or in combination with other therapeuticagents for treatment. In one embodiment, compounds of this invention maybe employed alone or in combination with chemotherapeutic agents. In oneembodiment, compounds of this invention may be employed alone or incombination with anti-inflammatory agents. The compounds of the presentinvention can be used in combination with one or more additional drugs,for example an anti-inflammatory compound or anti-cancer compound thatworks by a different mechanism of action. The second compound of thepharmaceutical combination formulation or dosing regimen preferably hascomplementary activities to the compound of this invention such thatthey do not adversely affect each other. Such molecules are suitablypresent in combination in amounts that are effective for the purposeintended. The compounds may be administered together in a unitarypharmaceutical composition or separately and, when administeredseparately this may occur simultaneously or sequentially in any order.Such sequential administration may be close in time or remote in time.

In certain embodiments, a compound of Formula I, or a subformula thereofis combined in a pharmaceutical combination formulation, or dosingregimen as combination therapy, with a second therapeutic compound thathas anti-inflammatory or anti-cancer properties or that is useful fortreating an inflammation, immune-response disorder, orhyperproliferative disorder (e.g., cancer). The second therapeutic agentmay be a NSAID (Non-Steroidal Anti-Inflammatory Drug) or otheranti-inflammatory agent. The second therapeutic agent may be achemotherapeutic agent. In one embodiment, a pharmaceutical compositionof this invention comprises a compound of Formula I, or a stereoisomer,geometric isomer, tautomer, solvate, metabolite, or pharmaceuticallyacceptable salt or prodrug thereof, in combination with a therapeuticagent such as an NSAID.

The combination therapy may provide “synergy” and prove “synergistic”,i.e. the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect may be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined, unit dosage formulation; (2) delivered byalternation or in parallel as separate formulations; or (3) by someother regimen. When delivered in alternation therapy, a synergisticeffect may be attained when the compounds are administered or deliveredsequentially, e.g. by different injections in separate syringes. Ingeneral, during alternation therapy, an effective dosage of each activeingredient is administered sequentially, i.e. serially, whereas incombination therapy, effective dosages of two or more active ingredientsare administered together.

Suitable dosages for any of the above coadministered agents are thosepresently used and may be lowered due to the combined action (synergy)of the newly identified agent and other chemotherapeutic agents ortreatments.

EXAMPLES

The invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention. These examples are not intended to limit thescope of the present invention, but rather to provide guidance to askilled artisan to prepare and use the compounds, compositions, andmethods of the present invention. While particular embodiments of thepresent invention are described, the skilled artisan will appreciatethat various changes and modifications can be made without departingfrom the spirit and scope of the invention.

The chemical reactions in the Examples described can be readily adaptedto prepare a number of other compounds of the invention, and alternativemethods for preparing the compounds of this invention are deemed to bewithin the scope of this invention. For example, the synthesis ofnon-exemplified compounds according to the invention can be successfullyperformed by modifications apparent to those skilled in the art, e.g.,by appropriately protecting interferring groups, by utilizing othersuitable reagents known in the art other than those described, and/or bymaking routine modifications of reaction conditions. Alternatively,other reactions disclosed herein or known in the art will be recognizedas having applicability for preparing other compounds of the invention.

Description of General Reaction Conditions

Commercially available reagents were purchased from suppliers such asAldrich Chemical Company, Lancaster, TCI or Maybridge, and were usedwithout further purification unless otherwise indicated.2-methylbut-3-yn-2-ol, 1-ethynylcyclopentan-1-ol and3-methoxy-3-methylbut-1-yne were readily available and purchased fromcommercial sources. The reactions set forth below were done generallyunder a positive pressure of nitrogen or argon or with a drying tube(unless otherwise stated), in anhydrous solvents, and the reactionflasks were typically fitted with rubber septa for the introduction ofsubstrates and reagents via syringe. Glassware was oven dried and/orheat dried. Column chromatography was conducted on a Biotage system(Isolera Four) having a silica gel column or, alternatively columnchromatography was carried out using an Isolute® silica gel cartridge(Biotage). ¹H NMR spectra were recorded on either on a Bruker DPXinstrument operating at 250 MHz or a Bruker DRX instrument operating at500 MHz. ¹H NMR spectra were obtained in deuterated CDCl₃, d₆-DMSO orCH₃OD (reported in ppm), using chloroform as the reference standard(7.25 ppm). When peak multiplicities are reported, the followingabbreviations are used: s (singlet), d (doublet), t (triplet), m(multiplet), br (broadened), dd (doublet of doublets), dt (doublet oftriplets). Coupling constants, when given, were reported in Hertz (Hz).When possible, product formations in the reaction mixtures weremonitored by LC-MS (Method B). LC-MS m/z data for the compoundsdescribed were obtained by LC-MS (Method A) unless otherwise stated.

LC-MS (Method A)

Column Waters Atlantis dC18 100 × 2.1 mm, 3 μm column 40° C. Mobilephase A—0.1% Formic acid (water) B—0.1% Formic acid (acetonitrile) Flowrate 0.6 ml/min Injection volume 3 μL Detector 215 nm and 254 nmGradient Time (mins) % B 0 5 5 100 5.4 100 5.42 5

LC-MS (Method B)

Column Waters Atlantis dC18 100 × 2.1 mm, 3 μm column Mobile phaseA—0.1% Formic acid (water) B—0.1% Formic acid (acetonitrile) Flow rate1.0 ml/min Injection volume 3 μL Detector 215 nm (nominal) Gradient Time(mins) % B 0 5 2.5 100 2.7 100 2.71 5 3.0 5

Reverse phase HPLC purification methods used anywhere from 0-100%acetonitrile in water and may contain 0.1% formic acid, 0.1% TFA or 0.2%ammonium hydroxide and used one of the following columns:

a) Waters Sunfire OBD C18 5 um, 30×150 mm column;b) Phenomenex Gemini Axia C18 5 um, 30×100 mm column;

c) Waters XBridge Prep C18 5 um, 19×100 mm; or

or using IntelFlash-1; Column, T3; mobile phase,acetonitrile/Water=10/90 increasing to acetonitrile/Water=95/5 within 16min; Detector, UV 254 nm

Alternatively, other reverse phase HPLC purification methods usedanywhere from 0-100% acetonitrile in water and may contain 0.1% formicacid, 0.1% TFA or 0.2% ammonium hydroxide and used one of the followingcolumns:

a) Waters Sunfire OBD C18 5 μm, 30×150 mm column or 19×150 column;b) Phenomenex Gemini Axia C18 5 μm, 30×100 mm column;

c) Waters XBridge Prep C18 5 μm, 19×100 mm; or

d) Phenomenex Luna C18 10 μm 25-200 column.

Chemical structures were named according to: vendor designation; IUPACconvention; J Chem for Excel, Version 5.3.8.14, ChemAxon Ltd. or Autonom2000 Name, MDL Inc. It is recognized by those skilled in the art that acompound may have more than one name, according to differentconventions.

Example 1 Preparation of4-[1-(2-aminopyrimidin-4-yl)-1H-indazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

Step 1—Synthesis of 4-(6-iodo-1H-indazol-1-yl)pyrimidin-2-amine (1-a1)and 4-(6-iodo-2H-indazol-2-yl)pyrimidin-2-amine (1-a2)

To a solution of 6-iodo-1H-indazole (500 mg, 1.95 mmol) in DMF (5 mL)was added NaH (60% oil dispersion) (125 mg, 3.11 mmol) at 0° C. Themixture was stirred at RT for 10 min before addition of4-chloropyrimidin-2-amine (504 mg, 3.89 mmol). Stirring was continued atRT for 18 hr then the mixture was heated at 50° C. for 2 hr. LCMS showedformation of a (1:1) mixture of (1-a1) and (1-a2). These isomers wereseparated as follows:

The reaction mixture was quenched by addition of water (5 mL).Extraction with EtOAc (3×5 mL) resulted in precipitation. Suctionfiltration gave 4-(6-iodo-2H-indazol-2-yl)pyrimidin-2-amine (1-a2) as apale brown solid: ¹H NMR (250 MHz, DMSO) δ 7.13 (2H, s), 7.28 (1H, d,J=5.33 Hz), 7.39 (1H, d, J=1.37 Hz), 7.67 (1H, dd, J=8.91, 0.69 Hz),8.21 (1H, d, J=0.91 Hz), 8.46 (1H, d, J=5.18 Hz), 9.12 (1H, d, J=1.07Hz). LC-MS: m/z=+337.90 (M+H)+.

The filtrate was washed with water (5 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. The residue was purified by flash chromatography(Isolute column, 50% EtOAc in heptanes) to give(6-iodo-1H-indazol-1-yl)pyrimidin-2-amine (1-a1) as a pale brown solid:¹H NMR (250 MHz, DMSO) δ 7.08 (1H, d, J=5.48 Hz), 7.11-7.16 (2H, m),7.69 (2H, dd, J=1.75, 0.99 Hz), 8.30 (1H, d, J=5.63 Hz), 8.47 (1H, d,J=0.76 Hz), 9.31 (1H, d, J=0.91 Hz) LC-MS: m/z=+337.90 (M+H)+.

Step 2: Synthesis of4-[1-(2-aminopyrimidin-4-yl)-1H-indazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol(1-b)

To a mixture of 4-(6-iodo-1H-indazol-1-yl)pyrimidin-2-amine (1-a1) (150mg, 0.285 mmol) and piperidine (1 mL) was addedtetrakis(triphenylphosphine)palladium (49.3 mg, 0.043 mmol), copper(I)iodide (8.1 mg, 0.043 mmol) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (1-1)(131 mg, 0.854 mmol). The reaction was purged with N₂ and stirred at RTfor 30 min. The reaction mixture was concentrated in vacuo and theresidue purified by reverse phase preparative HPLC to afford the titlecompound: ¹H NMR (500 MHz, DMSO) δ 1.95 (3H, s), 7.04 (2H, br. s.),7.08-7.13 (2H, m), 7.35 (1H, dd, J=8.20, 1.26 Hz), 7.70 (1H, d, J=3.15Hz), 7.79 (1H, d, J=3.15 Hz), 7.89 (1H, d, J=8.51 Hz), 8.30 (1H, d,J=5.67 Hz), 8.50 (1H, s), 8.91 (1H, s). LC-MS: m/z=+363.4 (M+H)+.

Example 2 Preparation of4-[1-(2-aminopyrimidin-4-yl)-1H-indazol-6-yl]-2-(1,3-oxazol-2-yl)but-3-yn-2-ol

Step 1—Synthesis of 4-(6-bromo-1H-indazol-1-yl)pyrimidin-2-amine

The title compound was prepared by procedure described in Example 1-al,by substituting 6-iodo-1H-indazole with 6-bromo-1H-indazole in Step 1:¹H NMR (500 MHz, DMSO) δ 7.08 (3H, d, J=5.52 Hz), 7.52 (1H, d, J=1.58Hz), 7.85 (1H, d, J=8.51 Hz), 8.30 (1H, d, J=5.36 Hz), 8.49 (1H, s),9.14 (1H, s); LC-MS: m/z=+289.6/291.6 (M+H)+.

Step 2—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-1H-indazol-6-yl]-2-(1,3-oxazol-2-yl)but-3-yn-2-ol

The title compound was prepared by adaption of procedure described inExample 1, by substituting 4-(6-iodo-1H-indazol-1-yl)pyrimidin-2-aminewith 4-(6-bromo-1H-indazol-1-yl)pyrimidin-2-amine in Step 2. Thereaction was carried out at 60° C. for 2 hr. The title compound,4-[1-(2-aminopyrimidin-4-yl)-1H-indazol-6-yl]-2-(1,3-oxazol-2-yl)but-3-yn-2-ol,was obtained: ¹H NMR (500 MHz, DMSO) δ 1.94 (3H, s), 6.79 (1H, s),6.99-7.16 (3H, m), 7.24 (1H, s), 7.37 (1H, dd, J=8.28, 1.18 Hz), 7.90(1H, d, J=8.20 Hz), 8.16 (1H, s), 8.31 (1H, d, J=5.52 Hz), 8.51 (1H, s),8.93 (1H, s); LC-MS: m/z=+347.5 (M+H)+.

Example 3

Examples in Table 3 were prepared by procedures described in eitherExample 1 or Example 2 by reacting4-(6-iodo-1H-indazol-1-yl)pyrimidin-2-amine (Example 1) or4-(6-bromo-1H-indazol-1-yl)pyrimidin-2-amine (Example 2) with theappropriate but-3-yn-2-ol intermediates.

TABLE 2 MS No. Structure Name ¹H NMR (M + H) T2-3.1

4-{6-[3-methoxy-3-(1,3- thiazol-2-yl)but-1-yn-1- yl]-1H-indazol-1-yl}pyrimidin-2-amine (500 MHz, DMSO) δ 1.96 (3 H, s), 3.42 (3 H, s), 7.13(3 H, br. s.), 7.45 (1 H, dd, J = 8.35, 0.95 Hz), 7.81 (1 H, d, J = 3.15Hz), 7.86 (1 H, d, J = 3.15 Hz), 7.93 (1 H, d, J = 8.35 Hz), 8.53 (1 H,s), 8.99 (1 H, s) 377.5 T2-3.2

4-[6-(3-methoxy-3- methylbut-1-yn-1-yl)-1H- indazol-1-yl]pyrimidin-2-amine (500 MHz, DMSO) δ 1.54 (6 H, s), 3.37 (3 H, s), 6.99-7.14 (3 H,m), 7.38 (1 H, dd, J = 8.20, 1.26 Hz), 7.88 (1 H, d, J = 8.20 Hz), 8.31(1 H, br. s.), 8.50 (1 H, d, J = 0.63 Hz), 8.92 (1 H, s) 308.2 T2-3.3

4-[1-(2-aminopyrimidin- 4-yl)-1H-indazol-6-yl]- 1,1-difluoro-2-methylbut-3-yn-2-ol (500 MHz, DMSO) δ 1.54 (3 H, s), 5.81-6.18 (1 H, m),6.47 (1 H, br. s.), 6.97-7.18 (3 H, m), 7.37 (1 H, dd, J = 8.20, 1.26Hz), 7.91 (1 H, d, J = 8.35 Hz), 8.31 (1 H, d, J = 5.52 Hz), 8.51 (1 H,d, J = 0.79 Hz), 8.94 (1 H, s) 330.4 T2-3.4

4-[1-(2-aminopyrimidin- 4-yl)-1H-indazol-6-yl]- 2-methylbut-3-yn-2-ol(500 MHz, DMSO) δ 1.53 (6 H, s), 5.55 (1 H, br. s.), 6.96-7.18 (3 H, m),7.33 (1 H, dd, J = 8.24, 1.22 Hz), 7.87 (1 H, d, J = 8.24 Hz), 8.30 (1H, d, J = 5.49 Hz), 8.49 (1 H, s), 8.88 (1 H, s) 294.4 T2-3.5

1-{2-[1-(2-aminopyrimidin- 4-yl)-1H-indazol-6- yl]ethynyl}cyclopentan-1-ol (500 MHz, DMSO) δ 1.68-1.80 (4 H, m), 1.93- 2.00 (4 H, m), 5.33-5.42 (1 H, m), 7.04 (2 H, br. s.), 7.10 (1 H, d, J = 5.49 Hz), 7.33 (1H, dd, J = 8.24, 1.37 Hz), 7.87 (1 H, dd, J = 8.24, 0.61 Hz), 8.30 (1 H,d, J = 5.49 Hz), 8.48 (1 H, d, J = 0.76 Hz), 8.88 (1 H, s) 320.1

Example 4 Preparation of4-[1-(2-amino-5-chloropyrimidin-4-yl)-1H-indazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

Step 1 Synthesis of 5-chloro-4-(6-iodo-1H-indazol-1-yl)pyrimidin-2-amine

To a solution of 6-iodo-1H-indazole (100 mg, 0.41 mmol) in DMF (3 mL)was added NaH (60% oil dispersion, 32 mg, 0.82 mmol) at 0° C. Themixture was stirred at 0° C. to RT for 10 min before addition of4,5-dichloropyrimidin-2-amine (134.4 mg, 0.82 mmol). The mixture wasstirred at 50° C. for 2 hr, then quenched with water and extracted withDCM (2×). The combined organic layers were dried over Na₂SO₄, filteredand concentrated in vacuo. LC-MS (Method B) indicated a mixture of titlecompound [67%, Retention time=2.11 min, m/z=+371.9/373.9 (M+H)+] and anisomeric by-product [10%, Retention time=2.07 min, m/z=+371.9/373.9(M+H)+]. Purification by flash chromatography (Isolute column, 50% EtOAcin heptane) afforded the title compound: ¹H NMR (500 MHz, DMSO) δ 7.31(2H, br. s.), 7.65 (1H, dd, J=8.51, 1.26 Hz), 7.71 (1H, d, J=8.20 Hz),8.45-8.48 (1H, m), 8.56-8.71 (1H, m), 8.61 (1H, s); LC-MS: m/z=+371.9(M+H)+.

Step 2—Synthesis of4-[1-(2-amino-5-chloropyrimidin-4-yl)-1H-indazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

To a mixture of 5-chloro-4-(6-iodo-1H-indazol-1-yl)pyrimidin-2-amine(170 mg, 0.46 mmol) and piperidine (1.2 mL) was addedtetrakis(triphenylphosphine)palladium (52.9 mg, 0.05 mmol), copper(I)iodide (8.7 mg, 0.05 mmol) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (1-1)(140.2 mg, 0.92 mmol). The reaction was purged with N₂ and stirred at RTfor 20 min. The reaction mixture was concentrated in vacuo and theresultant residue purified by flash chromatography (Isolute column, 1%MeOH in DCM), followed by reverse phase preparative HPLC to give thetitle compound as a solid: ¹H NMR (500 MHz, DMSO) δ 1.91 (3H, s), 7.09(1H, s), 7.23-7.39 (3H, m), 7.69 (1H, d, J=3.36 Hz), 7.78 (1H, d, J=3.20Hz), 7.90 (1H, d, J=8.24 Hz), 8.17 (1H, d, J=0.76 Hz), 8.43-8.53 (2H,m); LC-MS: m/z=+397.40 (M+H)+.

Example 5 Preparation of4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

Step 1—Synthesis of4-(6-bromo-3-methyl-1H-indazol-1-yl)pyrimidin-2-amine

To a solution of 6-bromo-3-methylindazole (300 mg, 1.42 mmol) in DMF (6mL) was added NaH (60% oil suspension) (91 mg, 2.27 mmol) at 0° C. Themixture was stirred at RT for 10 min before addition of4-chloropyrimidin-2-amine (368 mg, 2.84 mmol). Stirring continued at 60°C. for 2 hr. After standing at RT overnight the reaction mixture wasquenched by addition of water (10 mL). The mixture was extracted withEtOAc (2×15 mL). During the process of extraction solid formed wasremoved by suction filtration. The organic layer was washed with water(2×5 mL), dried over Na₂SO₄, filtered and concentrated in vacuo. Theresidue was triturated with EtOAc-heptane (1:1) to give the titleintermediate as a white solid: ¹H NMR (250 MHz, DMSO) δ 2.53-2.64 (3H,m), 6.69-7.21 (3H, m), 7.43-7.62 (1H, m), 7.76-7.89 (1H, m), 8.18-8.38(1H, m), 8.92-9.15 (1H, m); LC-MS: m/z=+303.95/305.65 (M+H).

Step 2—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

To a mixture of 4-(6-bromo-3-methyl-1H-indazol-1-yl)pyrimidin-2-amine(5-a) (240 mg, 0.489 mmol) and piperidine (1.2 mL) was addedtetrakis(triphenylphosphine)palladium (53.5 mg, 0.049 mmol), copper(I)iodide (9.3 mg, 0.049 mmol) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (1-1)(150 mg, 0.978 mmol). The reaction was purged with N₂ and stirred at 60°C. for 1.5 hr. The reaction mixture was concentrated in vacuo. EtOAc (2mL) was added to the residue and concentration in vacuo was repeated.The resultant residue was purified by flash chromatography (Isolutecolumn, 100% DCM to 3% MeOH in DCM) to afford the title compound as awhite solid: ¹H NMR (250 MHz, DMSO) δ 1.87-1.97 (3H, m), 2.56 (3H, s),6.91-7.00 (1H, m), 7.01-7.07 (1H, m), 7.10-7.23 (1H, m), 7.29-7.40 (1H,m), 7.65-7.73 (1H, m), 7.74-7.80 (1H, m), 7.81-7.90 (1H, m), 8.19-8.32(1H, m), 8.76-8.92 (1H, m); LC-MS: m/z=+377.5 (M+H)+.

Example 6 Preparation of4-[1-(2-aminopyrimidin-4-yl)-3-[(dimethylamino)methyl]-1H-indazol-6-yl]-2-methylbut-3-yn-2-ol

Step 1—Synthesis of 1-(6-bromo-1H-indazol-3-yl)-N,N-dimethylmethanamine

To a solution of 6-bromo-1H-indazole-3-carbaldehyde (300 mg, 1.33 mmol)in THF (1 mL) was added acetic acid (0.11 mL, 2 mmol), 2M dimethylaminein THF (1.33 mL, 2.66 mmol) and sodium triacetoxyborohydride (283 mg,1.33 mmol). The reaction was stirred at RT for 2 hr then allowed tostand at RT for 18 hr. The mixture was concentrated in vacuo, thendiluted with EtOAc (50 mL) and washed with 1M aqueous NaHCO₃ (10 mL).The organic layer was washed with brine (5 mL), followed by water (5mL). The organic layer was then dried (Na₂SO₄), filtered andconcentrated in vacuo to give the title compound as a beige solid: ¹HNMR (500 MHz, MeOD) δ 2.31 (6H, s), 3.85 (2H, s), 7.27 (1H, dd, J=8.67,1.58 Hz), 7.68-7.72 (1H, m), 7.77 (1H, d, J=8.67 Hz). LC-MS:m/z=+253.9/255.9 (M+H)+.

Step 2—Synthesis of4-{6-bromo-3-[(dimethylamino)methyl]-1H-indazol-1-yl}pyrimidin-2-amine

To a solution of (6-Bromo-1H-indazol-3-ylmethyl)-dimethyl-amine (523 mg,2.05 mmol) in DMF (8 mL) was added NaH (60% oil dispersion) (132 mg,3.29 mmol) at 0° C. The reaction mixture was allowed to warm up to RTand was stirred for 15 min. A solution of 4-chloropyrimidin-2-amine (533mg, 4.11 mmol) in DMF (3 mL) was added slowly. The resulting mixture wasstirred at 60° C. for 18 hr. When the reaction mixture was partitionedbetween EtOAc (25 mL) and water (10 mL), precipitation occurred. Thesolid was collected by suction filtration and was washed with EtOAc togive the title compound: ¹H NMR (500 MHz, DMSO) δ 2.22 (6H, s), 3.81(2H, s), 7.04 (1H, d, J=5.52 Hz), 7.06-7.19 (2H, m), 7.50 (1H, m, J=8.51Hz), 7.92 (1H, d, J=8.51 Hz), 8.27 (1H, d, J=5.52 Hz), 9.11 (1H, d,J=1.26 Hz); LC-MS: m/z=+348.9 (M+H)+.

Step 3—Synthesis of−[1-(2-aminopyrimidin-4-yl)-3-[(dimethylamino)methyl]-1H-indazol-6-yl]-2-methylbut-3-yn-2-ol

To a solution of4-{6-bromo-3-[(dimethylamino)methyl]-1H-indazol-1-yl}pyrimidin-2-amine(80 mg, 0.23 mmol) in piperidine (2 mL) was added 2-methyl-but-3-yn-2-ol(38.8 mg, 0.461 mmol), CuI (4.4 mg, 0.023 mmol) andtetrakis(triphenylphosphine)palladium (13.3 mg, 0.012 mmol). The mixturewas heated at 75° C. for 1 hr in a sealed tube. Volatiles were removedby concentration in vacuo. Purification by flash chromatography (Isolutecolumn, 100% DCM to 5% MeOH in DCM) afforded the title compound asyellow solid: ¹H NMR (500 MHz, DMSO) δ 1.53 (6H, s), 2.23 (6H, s), 3.80(2H, s), 5.51 (1H, s), 6.93-7.09 (2H, m), 6.97-7.04 (1H, m), 7.32 (1H,d, J=8.20 Hz), 7.93 (1H, s), 8.19-8.35 (1H, m), 8.84 (1H, s); LC-MS:m/z=+351.10 (M+H)+.

Example 7 Preparation of4-[1-(2-aminopyrimidin-4-yl)-3-(morpholin-4-ylmethyl)-1H-indazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

Step 1—Synthesis of 6-bromo-3-(morpholin-4-ylmethyl)-1H-indazole

The title compound was prepared by the procedure described in Example8-a by substituting 2M dimethylamine in THF with morpholine in Step 1:¹H NMR (250 MHz, CDCl₃) δ 2.49-2.68 (4H, m), 3.66-3.82 (4H, m), 3.93(2H, s), 7.25-7.32 (1H, m), 7.65 (1H, d, J=0.91 Hz), 7.78 (1H, d, J=8.98Hz), 8.17 (1H, br. s); LC-MS: m/z=+296.0/297.8 (M+H)+.

Step 2-Synthesis of4-[6-bromo-3-(morpholin-4-ylmethyl)-1H-indazol-1-yl]pyrimidin-2-amine

The title compound was prepared by the procedure described in Example8-b by substituting 1-(6-bromo-1H-indazol-3-yl)-N,N-dimethylmethanaminewith 6-bromo-3-(morpholin-4-ylmethyl)-1H-indazole in Step 2: ¹H NMR (250MHz, DMSO) δ 2.44 (4H, d, J=3.81 Hz), 3.55 (4H, br. s.), 3.87 (2H, s),7.02 (3H, d, J=5.63 Hz), 7.52 (1H, s), 7.95 (1H, s), 8.26 (1H, d, J=5.63Hz), 9.09 (1H, d, J=1.37 Hz); LC-MS: m/z=+389.0/391.0 (M+H)+.

Step 3—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-3-(morpholin-4-ylmethyl)-1H-indazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

The title compound was prepared by the procedure described in Example6-c by substituting4-{6-bromo-3-[(dimethylamino)methyl]-1H-indazol-1-yl}pyrimidin-2-aminewith4-[6-bromo-3-(morpholin-4-ylmethyl)-1H-indazol-1-yl]pyrimidin-2-amineand 2-methyl-but-3-yn-2-ol with 2-(1,3-thiazol-2-yl)but-3-yn-2-ol. Thereaction was carried out at 60° C. for 1.5 hr. Title compound wasobtained: ¹H NMR (500 MHz, DMSO) δ 1.93 (3H, s), 2.45 (4H, br. s.),3.55-3.57 (4H, m), 3.88 (2H, s), 6.98 (2H, br. s.), 7.05 (1H, d, J=5.52Hz), 7.12 (1H, s), 7.35 (1H, dd, J=8.35, 1.26 Hz), 7.68 (1H, d, J=3.31Hz), 7.78 (1H, d, J=3.31 Hz), 8.01 (1H, d, J=8.35 Hz), 8.27 (1H, d,J=5.52 Hz), 8.87 (1H, s); LC-MS: m/z=+462.1 (M+H)+.

Example 8 Preparation of1-(2-aminopyrimidin-4-yl)-1H-indazole-6-carbonitrile

To a solution of 1H-indazole-6-carbonitrile (200 mg, 1.40 mmol) in DMF(2 mL), was added NaH (60% oil dispersion) (89.4 mg, 2.24 mmol). Thereaction mixture was stirred for 10 min at RT before addition of4-chloropyrimidin-2-amine (362 mg, 2.79 mmol). The reaction mixture wasstirred at RT for 1 hr then heated at 50° C. in a sealed tube for 18 hr.LC-MS (Method B) indicated a mixture of desired product and aregiosiomer by-product [21%, Retention time=1.65 min, m/z=237.4 (M+H)+]and [29%, Retention time=1.43 min, m/z=237.4 (M+H)+]. The reaction wasquenched by addition of water (1 mL) and EtOAc (3 mL). The precipitatedsolid was collected by suction filtration: LC-MS (Method B): Retentiontime=1.65 min.

LC-MS (Method B) of the filtrate showed Retention time=1.43 min as themajor peak. Further trituration with EtOAc gave a second crop of solid,which was the title compound: ¹H NMR (500 MHz, MeOD) δ 7.29 (1H, d,J=5.65 Hz), 7.63 (1H, dd, J=8.24, 1.22 Hz), 8.03 (1H, dd, J=8.24, 0.46Hz), 8.29 (1H, d, J=5.80 Hz), 8.45 (1H, s), 9.45 (1H, s); LC-MS:m/z=+236.90 (M+H)+.

Example 9 Preparation ofN-[2-amino-4-(6-cyano-1H-indazol-1-yl)pyrimidin-5-yl]-3-methyloxetane-3-carboxamide

Step 1—Synthesis of 2-amino-5-nitro-3,4-dihydropyrimidin-4-one

Concentrated sulfuric acid (2.4 mL) was added to2-amino-3,4-dihydropyrimidin-4-one (1 g, 9.0 mmol). The mixture wasstirred and cooled in ice bath before dropwise addition of concentratednitric acid (0.56 mL). The mixture was stirred at RT for 30 min beforebeing heated at 70° C. for 2 hr. The mixture was allowed to cool to RTand was slowly added to water (10 mL), cooled in an ice bath. Theresultant precipitate was collected by suction filtration, washed withdiethyl ether (5 mL) and then thoroughly dried under high vacuum to givethe title compound: ¹H NMR (250 MHz, DMSO) δ 7.18 (1H, br. s.), 8.61(1H, br. s.), 8.81 (1H, s); LC-MS: m/z=+156.9 (M+H)+.

Step 2—Synthesis of 6-chloro-5-nitro-1,6-dihydropyrimidin-2-amine

A suspension mixture of 2-amino-5-nitro-3,4-dihydropyrimidin-4-one (1.5g, 9.61 mmol) and phosphorus oxychloride (27 mL, 0.29 mol) was heatedunder reflux (100° C.) for 18 hr. The reaction mixture turned into ayellow solution. The mixture was cooled to RT before being concentratedin vacuo. DCM (10 mL) was added and concentrated in vacuo was repeated.Ice (ca 5 g) was added, resulted in a sticky solid. DCM (20 mL) wasadded and the mixture was quenched by addition to an ice-cold saturatedaqueous NaHCO₃ solution (150 mL). The pH of mixture was adjusted tobasic by final addition of 2M aq K₂CO₃. Attempt to extract product withDCM resulted in emulsion formation. Emulsion was removed by suctionfiltration. The aqueous layer was extracted with EtOAc (3×50 mL). TheEtOAc extracts were combined with the DCM extract, dried over Na₂SO₄,filtered and concentrated in vacuo to afford the title compound as ayellow powder: ¹H NMR (500 MHz, DMSO) δ 8.40-8.48 (2H, m), 9.02 (1H, s).LC-MS: m/z=+174.9 (M+H)+.

Step 3—Synthesis of1-(2-amino-5-nitro-3,4-dihydropyrimidin-4-yl)-1H-indazole-6-carbonitrile

To a solution of 6-chloro-5-nitro-1,6-dihydropyrimidin-2-amine (538.5mg, 60% purity, 2.00 mmol) in DMF (10 mL) was added NaH (60% oilsuspension, 172 mg, 4.30 mmol) at 0° C. Mixture was stirred at RT for 10min before addition of 1H-indazole-6-carbonitrile (410 mg, 2.87 mmol).Stirring was continued at RT for 18 hr. The reaction mixture wasquenched with water (25 mL) cooled in an ice bath and extracted withEtOAc (3×20 mL). Insoluble solid formed during extraction was separatedout. Combined EtOAc extract was washed with water (20 mL), dried overNa₂SO₄, filtered and concentrated in vacuo. A portion (70 mg) of thecrude product was purified by reverse phase preparative HPLC to give thetitle compound: ¹H NMR (250 MHz, DMSO) δ 7.79 (1H, dd, J=8.22, 1.07 Hz),8.14 (1H, d, J=8.22 Hz), 8.20 (1H, br. s.), 8.33 (1H, br. s.), 8.65 (1H,s), 8.91 (1H, s), 9.03 (1H, s); LC-MS: m/z=+281.95 (M+H)+.

Step 4—Synthesis of1-(2,5-diaminopyrimidin-4-yl)-1H-indazole-6-carbonitrile

A mixture of1-(2-amino-5-nitro-3,4-dihydropyrimidin-4-yl)-1H-indazole-6-carbonitrile

(40% purity, 400 mg, 0.64 mmol) and tin (II) chloride (577 mg, 2.56mmol) in ethanol (15 mL) was heated at 60° C. for 2 hr then at 70° C.for 3 hr. LC-MS (Method B) showed 11% desired product and 74%degradation. The reaction mixture was concentrated in vacuo. The residuewas vigorously stirred with a mixture of saturated aqueous Rochelle salt(potassium sodium tartrate (20 mL), saturated aqueous NaHCO₃ (20 mL) andEtOAc (30 mL) for 30 min. The EtOAc layer was washed with brine (10 mL),dried over Na₂SO₄, filtered and concentrated in vacuo. The crude waspurified by column chromatography (Biotage) (100% EtOAc) to give thetitle compound as a pale yellow solid: ¹H NMR (250 MHz, DMSO) δ 5.40(2H, br. s.), 6.30 (2H, s), 7.69 (1H, dd, J=8.38, 1.22 Hz), 8.01-8.25(2H, m), 8.62 (1H, d, J=0.76 Hz), 9.31 (1H, s); LC-MS: m/z=+252.0(M+H)+.

Step 5—Synthesis ofN-[2-amino-4-(6-cyano-1H-indazol-1-yl)pyrimidin-5-yl]-3-methyloxetane-3-carboxamide

To a mixture of 3-methyloxetane-3-carboxylic acid (17 mg, 0.143 mmol)and HATU (54.5 mg, 0.143 mmol) was added a solution of1-(2,5-diaminopyrimidin-4-yl)-1H-indazole-6-carbonitrile (30 mg, 0.072mmol) in DMF (0.5 mL) followed by triethylamine (0.030 mL, 0.215 mmol).The mixture was stirred at RT for 10 min, then diluted with EtOAc (10mL) and washed with water (2×3 mL). The combined organic layer was driedover Na₂SO₄, filtered and concentrated in vacuo to give the crudecompound. The crude product was purified by flash chromatography(Isolute column, 90% EtOAc in heptane to 100% EtOAc and then 0.5%MeOH/EtOAc) to afford the title compound as a pale yellow solid: ¹H NMR(250 MHz, DMSO) δ 1.61 (3H, s), 4.31 (2H, d, J=5.94 Hz), 4.83 (2H, d,J=5.94 Hz), 7.20 (2H, br. s.), 7.65-7.92 (1H, m), 8.12 (1H, dd, J=8.22,0.76 Hz), 8.49 (1H, s), 8.64 (1H, d, J=0.91 Hz), 9.14 (1H, s), 9.70 (1H,s); LC-MS: m/z=+350.1 (M+H)+.

Example 10 Preparation ofN-(2-amino-4-{6-[3-hydroxy-3-(1,3-thiazol-2-yl)but-1-yn-1-yl]-1H-indazol-1-yl}pyrimidin-5-yl)-3-methyloxetane-3-carboxamide

Step 1—Synthesis of 4-(6-iodo-1H-indazol-1-yl)-5-nitropyrimidin-2-amine

To a solution of 6-iodo-1H-indazole (537 mg, 2.20 mmol) in DMF (16 mL)was added NaH (60% oil dispersion) (132 mg, 3.30 mmol) at 0° C. Mixturewas stirred at RT for 10 min before addition of a portion of6-chloro-5-nitro-1,6-dihydropyrimidin-2-amine (60% pure, 500 mg, 1.71mmol). The mixture was stirred at RT for 20 min. Another portion of NaH(60% oil dispersion) (132 mg, 3.30 mmol) was added at RT. After 10 min,another portion of 6-chloro-5-nitro-1,6-dihydropyrimidin-2-amine (60%pure, 300 mg, 1.03 mmol) was added. Stirring continued for 30 min. Thereaction mixture was cooled in an ice bath before quenching with water.The mixture was acidified by addition of 1 M aq HCl then the pH wasadjusted to 8-9 by dropwise addition of saturated aq NaHCO₃.

The mixture was further diluted with water (20 mL) and extracted withEtOAc (20 mL×3). During the first extraction with EtOAc the insolublesolid was removed by suction filtration. The combined EtOAc layer waswashed with water (20 mL), dried over Na₂SO₄ filtered and concentratedin vacuo to give the crude title compound: LC-MS (Method B): m/z=+382.9(M+H)+, (purity=45%) This intermediate was used in the next step withoutfurther purification.

Step 2—Synthesis of 4-(6-iodo-1H-indazol-1-yl)pyrimidine-2,5-diamine

To a suspension of 4-(6-iodo-1H-indazol-1-yl)-5-nitropyrimidin-2-amine(200 mg, 45% purity, 0.236 mmol) in a mixture of methanol (4 mL), DMF (3mL) and water (3 mL) was added sodium dithionite (205 mg, 1.178 mmol)and sodium bicarbonate (99 mg, 1.178 mmol). The suspension was stirredat RT for 2 hr. After 2 hr LC-MS (Method B) showed 11% of desiredproduct, 15% of starting4-(6-iodo-1H-indazol-1-yl)-5-nitropyrimidin-2-amine (16-a) and 67% ofdegraded by-product. The reaction mixture was diluted with EtOAc (30 mL)and washed with water (2×10 mL), then dried over Na₂SO₄, filtered andconcentrated in vacuo to give the crude title compound; m/z=+352.9(M+H)+, (purity=11%). This intermediate was used in the next stepwithout further purification.

Step 3—Synthesis ofN-[2-amino-4-(6-iodo-1H-indazol-1-yl)pyrimidin-5-yl]-3-methyloxetane-3-carboxamide

To a mixture of 3-methyloxetane-3-carboxylic acid (8.7 mg, 0.075 mmol)and HATU (28.5 mg, 0.075 mmol) was added a solution of crude4-(6-iodo-1H-indazol-1-yl)pyrimidine-2,5-diamine (11% purity, 120 mg,0.037 mmol) in DMF (0.5 mL) followed by triethylamine (0.016 mL, 0.112mmol). The mixture was stirred at RT for 10 min, then diluted with EtOAc(10 mL) and washed with water (2×3 mL). The combined organic layer wasdried over Na₂SO₄, filtered and concentrated in vacuo to give the crudecompound. Purification by flash chromatography (Isolute column, 100% DCMto 3% MeOH in DCM) gave the title compound; m/z=+451.30 (M+H)+,(purity=76%). This intermediate was used in the next step withoutfurther purification.

Step 4—Synthesis ofN-(2-amino-4-{6-[3-hydroxy-3-(1,3-thiazol-2-yl)but-1-yn-1-yl]-1H-indazol-1-yl}pyrimidin-5-yl)-3-methyloxetane-3-carboxamide

To a mixture ofN-[2-amino-4-(6-iodo-1H-indazol-1-yl)pyrimidin-5-yl]-3-methyloxetane-3-carboxamide(76% purity, 20 mg, 0.034 mmol) and piperidine (0.1 mL) was addedtetrakis(triphenylphosphine)palladium (7.8 mg, 0.007 mmol), copper(I)iodide (1.2 mg, 0.007 mmol) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (1-1)(10.3 mg, 0.068 mmol). The reaction was purged with N₂ and stirred at RTfor 2 hr. Reaction mixture was concentrated in vacuo. Purification byflash chromatography (Isolute column, 100% DCM to 2% MeOH-DCM) followedby recrystallization (1:1 MeOH-EtOAc mixture) gave the title compound:¹H NMR (500 MHz, MeOD) δ 1.73 (3H, s), 1.98 (3H, s), 4.47 (2H, d, J=5.99Hz), 5.01 (2H, d, J=6.15 Hz), 7.43 (1H, dd, J=8.28, 1.18 Hz), 7.57 (1H,d, J=3.31 Hz), 7.79 (1H, d, J=3.31 Hz), 7.83 (1H, d, J=8.35 Hz), 8.39(1H, s), 8.82 (1H, s), 8.92 (1H, s); m/z=+476.1 (M+H)+.

Example 11 Preparation of1-{4-[(2-methoxypyridin-3-yl)amino]-1,3,5-triazin-2-yl}-1H-indazole-6-carbonitrile

Step 1—Synthesis of4-chloro-N-(2-methoxypyridin-3-yl)-1,3,5-triazin-2-amine

To a solution of 2,4-dichloro-1,3,5-triazine (265.77 mg, 1.77 mmol) inTHF (5 mL) was added DIPEA (0.266 mL, 1.61 mmol) followed by2-methoxypyridin-3-amine (200 mg, 1.61 mmol). The resultant mixture wasstirred at RT for 2 hr, then DCM was added and the organics washed withwater (×²) and 0.5M aqueous HCl solution. Combined organics were driedover Na₂SO₄, filtered and concentrated in vacuo to give a beige solid:¹H NMR (250 MHz, DMSO) δ 3.88 (3H, s), 7.05 (1H, dd, J=7.54, 4.95 Hz),7.86 (1H, dd, J=7.61, 1.68 Hz), 8.07 (1H, dd, J=4.95, 1.75 Hz), 8.56(1H, s), 10.14 (1H, s); m/z=+238.0/239.9 (M+H)+.

Step 2—Synthesis of1-{4-[(2-methoxypyridin-3-yl)amino]-1,3,5-triazin-2-yl}-1H-indazole-6-carbonitrile

To a solution of 1H-indazole-6-carbonitrile (70 mg, 0.49 mmol) in DMF (5mL) was added NaH (60% oil dispersion, 39.12 mg, 0.98 mmol) at 0° C. Thereaction mixture was stirred at 0° C. for 10 minutes before the additionof 4-chloro-N-(2-methoxypyridin-3-yl)-1,3,5-triazin-2-amine (139.45 mg,0.59 mmol). Stirring at RT was continued for 2 hr. The reaction mixturewas then quenched with water and EtOAc was added. Precipitate formed wascollected by suction filtration, then redissolved in DCM and washed withwater. Further trituration (9:1 mixture of heptane/Et₂O) gave the titlecompound: ¹H (250 MHz, CDCl₃, VT @ 323K) δ 4.10 (3H, s), 7.06 (1H, br.s.), 7.60 (1H, dd, J=8.22, 1.37 Hz), 7.91 (1H, dd, J=8.22, 0.76 Hz),7.97 (2H, d), 8.42 (1H, d, J=0.76 Hz), 8.74 (1H, dd, J=7.84, 1.60 Hz),8.86 (1H, s), 9.20 (1H, s); m/z=+345.0 (M+H)+.

Example 12 Preparation of4-(6-bromo-1H-indazol-1-yl)-N-(2-methoxypyridin-3-yl)-1,3,5-triazin-2-amine

To a solution of 6-bromo-1H-indazole (172 mg, 0.87 mmol) in DMF (8 mL)was added NaH (60% in oil, 69.8 mg, 1.75 mmol) at 0° C. The reactionmixture was stirred at 0° C. for 10 minutes before the addition of4-chloro-N-(2-methoxypyridin-3-yl)-1,3,5-triazin-2-amine (311.18 mg,1.31 mmol). Stirring was continued at RT for 2 hr. The reaction mixturewas quenched with water and EtOAc added. The resultant precipitate wascollected and further drying under vacuum gave the title compound as abeige solid; ¹H NMR (250 MHz, CDCl₃) δ 4.09 (3H, s), 7.05 (1H, d, J=2.28Hz), 7.50 (1H, dd, J=8.53, 1.68 Hz), 7.62-7.70 (1H, m), 7.88-8.09 (2H,m), 8.30 (1H, d, J=0.76 Hz), 8.74 (1H, dd, J=7.77, 1.68 Hz), 8.83 (1H,s), 9.01 (1H, s); LC-MS: m/z=+397.9/399.8 (M+H)+.

Example 13 Preparation of4-(1-{4-[(2-methoxypyridin-3-yl)amino]-1,3,5-triazin-2-yl}-1H-indazol-6-yl)-2-methylbut-3-yn-2-ol

Step 1—Synthesis of4-(6-iodo-1H-indazol-1-yl)-N-(2-methoxypyridin-3-yl)-1,3,5-triazin-2-amine

The title compound was prepared by the procedure described in Example 12by substituting 6-bromo-1H-indazole with 6-iodo-1H-indazole; ¹H NMR (500MHz, CDCl₃) δ 4.06 (3H, s), 6.88-7.24 (1H, m), 7.52 (1H, d, J=8.35 Hz),7.67 (1H, dd, J=8.35, 0.79 Hz), 7.80-8.16 (2H, m), 8.29 (1H, d, J=0.63Hz), 8.64-8.91 (2H, m), 9.03-9.34 (1H, m); LC-MS (Method B): m/z=+446.0(M+H)+.

Step 2—Synthesis of4-(1-{4-[(2-methoxypyridin-3-yl)amino]-1,3,5-triazin-2-yl}-1H-indazol-6-yl)-2-methylbut-3-yn-2-ol

To a pressure tube was added4-(6-iodo-1H-indazol-1-yl)-N-(2-methoxypyridin-3-yl)-1,3,5-triazin-2-amine(100 mg, 0.22 mmol), followed by triethylamine (0.7 mL) and THF (0.7mL). Copper(I) iodide (4.28 mg, 0.022 mmol), PdCl₂(PPh₃)₂ (15.76 mg,0.022 mmol) and 2-methylbut-3-yn-2-ol (0.04 ml, 0.45 mmol) were thenadded and the reaction vessel was sealed and stirred at RT for 1 hr.

The reaction was concentrated in vacuo and DCM was added. The organicswere washed with 0.1M aq HCl, water and brine. Combined organics weredried over Na₂SO₄, filtered and concentrated in vacuo to give a redsolid which was purified by flash chromatography (Isolute column, 1%MeOH in DCM to 2.5% MeOH in DCM). Further trituration (10% diethyl etherin heptane) afforded the title compound as a red solid; ¹H NMR (250 MHz,CDCl₃, VT @ 323K) δ 1.70 (6H, s), 2.15 (1H, br. s.), 4.09 (3H, s), 7.04(1H, br. s.), 7.33-8.92 (7H, m); LC-MS: m/z=+401.4 (M+H)+.

Example 14 Preparation of4-[1-(2-aminopyrimidin-4-yl)-1H-1,3-benzodiazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

Step 1—Synthesis of N-(5-bromo-2-nitrophenyl)-2-chloropyrimidin-4-amine

To a solution of 2-chloropyrimidin-4-amine (8.83 g, 68.18 mmol) in THF(250 mL) at 0° C. was added sodium hydride (60% dispersion in oil, 4.36g, 181.82 mmol) portionwise. The reaction mixture was stirred at 0° C.to RT for 10 minutes before addition of 4-bromo-2-fluoro-1-nitrobenzene(10 g, 45.45 mmol). The reaction mixture was stirred at 65° C. for 1 hr,then after cooling to RT, water was added resulting in formation of ayellow precipitate. The solid was collected by suction filtration andwas washed with water. The filtrate was extracted with DCM. The organicswere washed with water, dried over Na₂SO₄, filtered and concentrated invacuo. The residue was purified by flash chromatography (Isolute column,1% MeOH in DCM) then combined with the solid collected by suctionfiltration to give the title compound: ¹HNMR (250 MHz, DMSO) δ 6.91 (1H,d, J=5.79 Hz), 7.61 (1H, dd, J=8.76, 2.21 Hz), 7.91-8.05 (2H, m), 8.29(1H, d, J=5.79 Hz), 10.40 (1H, s); LC-MS: m/z=+328.9, 330.8 (M+H)+.

Step 2—Synthesis of 4-N-(5-bromo-2-nitrophenyl)pyrimidine-2,4-diamine

To a solution of N-(5-bromo-2-nitrophenyl)-2-chloropyrimidin-4-amine (6g, 18.21 mmol) in 2-propanol (70 mL), in a pressure vessel, wascarefully added ammonium hydroxide solution (150 mL) at RT. The reactionvessel was sealed and stirred at 90° C. (at 4.5 bar pressure) for 20 hr.The reaction mixture was cooled to 0° C. The resulting precipitate wascollected by vacuum filtration, washed with water and dried in thevacuum oven to afford the title compound as an orange solid: ¹H NMR (250MHz, DMSO) δ 6.17 (1H, d, J=5.63 Hz), 6.34 (2H, br. s.), 7.39 (1H, dd,J=8.83, 1.98 Hz), 7.89-7.99 (2H, m), 8.34 (1H, d, J=2.13 Hz), 9.62 (1H,s); LC-MS: m/z+309.9, 311.7 (M+H)+.

Step 3—Synthesis of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine

To a solution of 4-N-(5-bromo-2-nitrophenyl)pyrimidine-2,4-diamine (5.06g, 16.32 mmol) in ethanol (110 mL) was added tin(II) chloride dihydrate(12.89 g, 57.11 mmol). The reaction mixture was stirred at 65° C. for 2hr. The reaction mixture was evaporated to dryness and ice-water added.The pH of the mixture was adjusted to 10 using saturated aqueous Na₂CO₃solution. EtOAc was added followed by saturated aqueous Rochelles salt(potassium sodium tartrate). The resulting mixture was stirred untilseparate layers were observed. The organic layer was extracted and theextraction repeated (2×) with EtOAc and DCM. Combined organic layer werewashed with brine, dried over Na₂SO₄, filtered and concentrated in vacuoto give the title compound as a pale yellow solid: ¹H NMR (250 MHz,DMSO) δ 5.05 (2H, br. s), 5.79 (1H, d, J=5.79 Hz), 6.08 (2H, br. s),6.68 (1H, d, J=8.53 Hz), 7.02 (1H, dd, J=8.60, 2.36 Hz), 7.36 (1H, d,J=2.28 Hz), 7.75 (1H, d, J=5.63 Hz), 8.15 (1H, s); LC-MS: m/z=+279.9,281.9 (M+H)+.

Step 4—Synthesis of 4-(6-bromo-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine

To a solution of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (750mg, 2.68 mmol) in mixture of methanol (7 mL) and THF (30 mL) was addedtrimethyl orthoformate (8.81 ml, 80.32 mmol) and TsOH (0.04 ml, 0.27mmol). The reaction mixture was stirred at 70° C. for 1 h. Then anotherportion of trimethyl orthoformate (4.4 ml, 40.16 mmol) was added.Stirring at 70° C. was continued for another 6 hr. The reaction mixturewas allowed to cool down to RT then a saturated aqueous solution ofNaHCO₃ was added. The product was extracted into DCM (×3) and thecombined organic layers were washed with brine and dried over Na₂SO₄,filtered and concentrated in vacuo to give the title compound; ¹H NMR(500 MHz, DMSO) δ 7.08-7.24 (3H, m), 7.50 (1H, dd, J=8.51, 1.89 Hz),7.71 (1H, d, J=8.51 Hz), 8.37 (1H, d, J=5.52 Hz), 8.83 (1H, d, J=1.73Hz), 9.08 (1H, s); LC-MS (Method B): m/z=+289.9, 291.8 (M+H)+. Thiscompound, with LC-MS purity=70%, was used in the next step withoutfurther purification.

Step 5—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-1H-1,3-benzodiazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

To a pressure tube was added4-(6-bromo-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine (70% purity, 790mg, 1.91 mmol), followed by piperidine (4 mL),tetrakis(triphenylphosphine)palladium (220 mg, 0.19 mmol), copper(I)iodide (36.3 mg, 0.19 mmol)) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol(584.04 mg, 3.81 mmol). The reaction was capped and stirred at 75° C.for 3.5 hr. The reaction mixture was concentrated in vacuo and purifiedby flash chromatography (Isolute column, 2% MeOH in DCM to 3% MeOH inDCM) followed by reverse phase preparative HPLC to give the titlecompound as a pale yellow solid: ¹H NMR (500 MHz, DMSO) δ 1.92 (3H, s),7.03 (1H, br. s.), 7.08-7.20 (3H, m), 7.38 (1H, dd, J=8.35, 1.58 Hz),7.69 (1H, d, J=3.15 Hz), 7.74 (1H, d, J=8.35 Hz), 7.78 (1H, d, J=3.31Hz), 8.38 (1H, d, J=5.52 Hz), 8.56 (1H, d, J=0.95 Hz), 9.08 (1H, s);LC-MS: m/z=+363.4 (M+H)+.

Example 15

Examples in Table 3 were prepared by procedure described in Example 14by reacting 4-(6-bromo-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine (14-d)with the appropriate but-3-yn-2-ol intermediates.

TABLE 3 MS No. Structure Name ¹H NMR (M + H) T3-15.1

4-[1-(2-aminopyrimidin- 4-yl)-1H-1,3- benzodiazol-6-yl]- 2-methylbut-3-yn-2-ol (500 MHz, DMSO) δ 1.51 (6 H, s), 5.46 (1 H, br. s.), 7.07-7.25(3 H, m), 7.35 (1 H, dd, J = 8.35, 1.58 Hz), 7.72 (1 H, d, J = 8.35 Hz),8.38 (1 H, d, J = 5.52 Hz), 8.55 (1 H, d, J = 0.95 Hz), 9.07 (1 H, s)294.4 T3-15.2

4-[1-(2-aminopyrimidin- 4-yl)-1H-1,3- benzodiazol-6-yl]- 1,1-difluoro-2-methylbut-3-yn-2-ol (500 MHz, DMSO) δ 1.52 (3 H, s), 5.83-6.09 (1 H, m),6.43 (1 H, s), 7.14 (1 H, d, J = 5.67 Hz), 7.17 (2 H, br. s.), 7.40 (1H, dd, J = 8.20, 1.58 Hz), 7.76 (1 H, d, J = 8.20 Hz), 8.39 (1 H, d, J =5.52 Hz), 8.61 (1 H, d, J = 0.95 Hz), 9.11 (1 H, s) 330.4 T3-15.3

4-[1-(2-aminopyrimidin- 4-yl)-1H-1,3- benzodiazol-6-yl]-1,1,1-trifluoro-2- methylbut-3-yn-2- ol (500 MHz, DMSO) δ 1.67 (3 H, s),7.13-7.16 (2 H, m), 7.19 (2 H, br. s.), 7.43 (1 H, dd, J = 8.35, 1.58Hz), 7.78 (1 H, d, J = 8.35 Hz), 8.39 (1 H, d, J = 5.36 Hz), 8.65 (1 H,d, J = 0.95 Hz), 9.13 (1 H, s) 348.4 T3-15.4

4-[1-(2-aminopyrimidin- 4-yl)-1H-1,3- benzodiazol-6-yl]-2-(1,3-oxazol-2- yl)but-3-yn-2-ol (500 MHz, DMSO) δ 1.92 (3 H, s), 6.73(1 H, s), 7.13 (1 H, d, J = 5.67 Hz), 7.18 (2 H, br. s), 7.23 (1 H, s),7.39 (1 H, dd, J = 8.35, 1.58 Hz), 7.75 (1 H, d, J = 8.35 Hz), 8.15 (1H, d, J = 0.79 Hz), 8.38 (1 H, d, J = 5.52 Hz), 8.60 (1 H, d, J = 0.95Hz), 9.11 (1 H, s) 347.4

Example 16 Preparation of1-(2-aminopyrimidin-4-yl)H-1,3-benzodiazole-6-carbonitrile

To a round bottom flask equipped with a condenser and nitrogen bubblerattached to a bleach scrubber bath was added4-(6-bromo-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine (90% purity, 83 mg,0.26 mmol) and zinc cyanide (30.23 mg, 0.26 mmol) in de-gassed DMF (2mL). Tetrakis(triphenylphosphine)palladium (29.75 mg, 0.03 mmol) wasthen added and the reaction heated stirred at 100° C. under nitrogen for30 min. The reaction mixture was allowed to cool to RT and poured intosaturated aqueous ammonium chloride (6 mL) and extracted into DCM (×2).The combined organics were dried over Na₂SO₄, filtered and concentratedin vacuo. The residue was combined with the precipitate formed duringthe aqueous work up process and was purified by flash chromatography(Isolute column, 10% MeOH in DCM) to afford the title compound as a palebeige solid; ¹H NMR (500 MHz, DMSO) δ 6.90-7.42 (3H, m), 7.76 (1H, dd,J=8.35, 1.58 Hz), 7.94 (1H, d, J=8.04 Hz), 8.40 (1H, d, J=5.52 Hz), 9.20(1H, d, J=0.95 Hz), 9.33 (1H, s); LC-MS: m/z=+236.95 (M+H)+.

Example 17 Preparation of4-[1-(2-aminopyrimidin-4-yl)-2-methyl-1H-1,3-benzodiazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

Step 1—Synthesis of4-(6-bromo-2-methyl-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine

To a solution of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (300mg, 1.07 mmol) in a mixture of methanol (5 mL) and THF (20 mL) was addedtrimethyl orthoacetate (2.02 ml, 0.02 mol) and TsOH (0.02 ml, 0.11mmol). The reaction mixture was stirred at 70° C. for 40 min thenallowed to stand at RT for 3 days. A saturated aqueous solution ofNaHCO₃ was added. The product was extracted into DCM (×3) and theorganic layers were washed with brine and then dried with Na₂SO₄,filtered and concentrated in vacuo. The residue was purified by flashchromatography (Isolute column, 1-2% MeOH in DCM) to give the titlecompound as a yellow solid; ¹H NMR (500 MHz, DMSO) δ 2.67 (3H, s), 6.88(1H, d, J=5.20 Hz), 7.13 (2H, br. s.), 7.41 (1H, dd, J=8.51, 1.89 Hz),7.58 (1H, d, J=8.51 Hz), 7.86 (1H, d, J=1.89 Hz), 8.48 (1H, d, J=5.20Hz); LC-MS: m/z=+303.9, 305.7 (M+H)+.

Step 2—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-2-methyl-1H-1,3-benzodiazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

The title compound was prepared by procedure described in Example 20 bysubstituting 4-(6-bromo-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine with4-(6-bromo-2-methyl-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine in Step 5:¹H NMR (500 MHz, DMSO) δ 1.87 (3H, s), 2.67 (3H, s), 6.88 (1H, d, J=5.20Hz), 7.00 (1H, s), 7.12 (1H, br. s.), 7.29 (1H, dd, J=8.28, 1.50 Hz),7.61 (1H, d, J=8.35 Hz), 7.64 (1H, d, J=0.79 Hz), 7.67 (1H, d, J=3.31Hz), 7.76 (1H, d, J=3.31 Hz), 8.48 (1H, d, J=5.20 Hz); LC-MS:m/z=+377.45 (M+H)+.

Example 18 Preparation of4-[1-(2-aminopyrimidin-4-yl)-2-cyclopropyl-1H-1,3-benzodiazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

Step 1—Synthesis of4-(6-bromo-2-cyclopropyl-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine

To a solution of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (400mg, 1.43 mmol) in DMF (4 mL) were added cyclopropanecarbaldehyde (130mg, 1.86 mmol) and oxone (527 mg, 0.86 mmol). The reaction was stirredat RT for 3 days. The mixture was diluted with EtOAc (20 mL) and washedwith water. The aqueous layer was extracted with more EtOAc. Thecombined organics were dried over Na₂SO₄, filtered and concentrated invacuo. Purification by flash chromatography (Isolute column, 100% DCM to2% MeOH/DCM) afforded the title compound as an orange solid: ¹H NMR (500MHz, MeOD) δ 1.16-1.24 (2H, m), 1.24-1.29 (2H, m), 2.32-2.48 (1H, m),6.98 (1H, d, J=5.36 Hz), 7.41-7.45 (1H, m), 7.47-7.52 (1H, m), 7.90 (1H,d, J=1.89 Hz), 8.51 (1H, d, J=5.20 Hz); LC-MS (Method B): m/z=+330.0,331.8 (M+H)+.

Step 2—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-2-cyclopropyl-1H-1,3-benzodiazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

The title compound was prepared by adaptation of procedure described inExample 14 by substituting4-(6-bromo-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine with4-(6-bromo-2-cyclopropyl-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine inStep 5: ¹H NMR (500 MHz, DMSO) δ 1.07-1.14 (2H, m), 1.14-1.21 (2H, m),1.86 (3H, s), 2.30-2.40 (1H, m), 6.91 (1H, d, J=5.04 Hz), 7.02 (1H,br.s.), 7.19 (2H, br. s.), 7.23-7.30 (1H, m), 7.55 (1H, d, J=8.20 Hz),7.61-7.65 (1H, m), 7.68 (1H, d, J=3.31 Hz), 7.76 (1H, d, J=3.15 Hz),8.37-8.61 (1H, m); LC-MS: m/z=+403.5 (M+H)+.

Example 19 Preparation of4-[1-(2-aminopyrimidin-4-yl)-2-cyclopropyl-1H-1,3-benzodiazol-6-yl]-2-methylbut-3-yn-2-ol

The title compound was prepared by procedure described in Example 25 bysubstituting 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (1-1) with2-methylbut-3-yn-2-ol (1-6) in Step 2: ¹H NMR (500 MHz, DMSO) δ1.08-1.15 (2H, m), 1.14-1.21 (2H, m), 1.47 (6H, s), 2.30-2.40 (1H, m),5.42 (1H, s), 6.91 (1H, d, J=5.20 Hz), 7.17 (2H, s), 7.21-7.28 (1H, m),7.54 (1H, d, J=8.35 Hz), 7.60-7.64 (1H, m), 8.51 (1H, d, J=5.20 Hz);LC-MS: m/z=+334.5 (M+H)+.

Example 20 Preparation of1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(1,3-thiazol-2-yl)but-1-yn-1-yl]-2,3-dihydro-1H-1,3-benzodiazol-2-one

Step 1—Synthesis of1-(2-aminopyrimidin-4-yl)-6-bromo-2,3-dihydro-1H-1,3-benzodiazol-2-one

To a solution of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (400mg, 1.43 mmol) in DMF (4 mL) was added N,N′-carbonyldiimidazole (255 mg,1.57 mmol). The reaction was stirred at 80° C. overnight. Anotherportion of N,N′-carbonyldiimidazole (69 mg, 0.43 mmol) was added andheating was continued for another 2 hr at 80° C. The reaction mixturewas concentrated in vacuo, diluted with water (10 mL) and extracted withethyl acetate (2×20 mL). The organics were dried over Na₂SO₄, filteredand concentrated in vacuo. The resulting yellow solid was slurried inethyl acetate and filtered off to give the title compound as a yellowsolid: ¹H (500 MHz, DMSO) δ 6.93 (2H, br. s.), 7.00 (1H, d, J=8.35 Hz),7.31 (1H, d, J=10.25 Hz), 7.45 (1H, d, J=5.67 Hz), 8.25 (1H, d, J=5.52Hz), 8.58 (1H, s); LC-MS: m/z=+306.0, 307.9 (M+H)+.

Step 2—Synthesis of1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(1,3-thiazol-2-yl)but-1-yn-1-yl]-2,3-dihydro-1H-1,3-benzodiazol-2-one

To a solution of1-(2-aminopyrimidin-4-yl)-6-bromo-2,3-dihydro-1H-1,3-benzodiazol-2-one(230 mg, 0.751 mmol) in EtOAc was added charcoal (5 mol %). The mixturewas stirred at RT for 20 min then filtered and concentrated in vacuo. Tothe residue in a sealed tube was added 2-(1,3-thiazol-2-yl)but-3-yn-2-ol(230 mg, 1.50 mmol), piperidine (2 mL),tetrakis(triphenylphosphine)palladium (43.4 mg, 0.038 mmol) andcopper(I) iodide (14.3 mg, 0.075 mmol). The reaction mixture was thenheated at 75° C. for 18 hr then partitioned between EtOAc (15 mL) andwater (2 mL). The organic layer was concentrated in vacuo and theresidue purified by reverse phase preparative HPLC to afford the titlecompound: ¹H NMR (500 MHz, DMSO) δ 1.90 (3H, s), 6.92 (2H, s), 6.95 (1H,s), 7.04 (1H, d, J=8.04 Hz), 7.21 (1H, dd, J=8.04, 1.42 Hz), 7.40 (1H,d, J=5.52 Hz), 7.68 (1H, d, J=3.31 Hz), 7.77 (1H, d, J=3.15 Hz),8.26-8.36 (2H, m), 11.57 (1H, br. s.); LC-MS: m/z=+379.0 (M+H)+.

Example 21 Preparation of1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-2,3-dihydro-1H-1,3-benzodiazol-2-one

The title compound was prepared by adaptation of procedure described inExample 20 by substituting 2-(1,3-thiazol-2-yl)but-3-yn-2-ol with2-methylbut-3-yn-2-ol in Step 2; ¹H NMR (500 MHz, DMSO) δ1.49 (6H, s),5.39 (1H, s), 6.92 (2H, br. s.), 7.03 (1H, d, J=8.04 Hz), 7.18 (1H, dd,J=8.04, 1.58 Hz), 7.42 (1H, d, J=5.67 Hz), 8.25-8.35 (2H, m), 11.54 (1H,br. s.); LC-MS: m/z=+310.4 (M+H)+.

Example 22

The following intermediates (1-1 to 1-4) in Table 4 were prepared bymodifying procedures described in WO 2009/158011.

TABLE 4 No Structure Name 1H NMR MS (M + H) T4-I.1

2-(1,3-thiazol-2-yl)but- 3-yn-2-ol (250 MHz, CDCl₃) δ 1.97 (3 H, s),2.70 (1 H, s), 3.92 (1 H, br. s.), 7.34 (1 H, d, J = 3.20 Hz), 7.76 (1H, d, J = 3.20 Hz) 153.9 T4-I.2

2-(1,3-oxazol-2-yl)but- 3-yn-2-ol (250 MHz, CDCl₃) δ 1.94 (3 H, s), 2.66(1 H, s), 3.90 (1 H, br. s.), 7.13 (1 H, d, J = 0.76 Hz), 7.67 (1 H, d,J = 0.76 Hz) 137.9 T4-I.3

1,1-difluoro-2-methylbut- 3-yn-2-ol (250 MHz, CDCl₃) δ 1.53- 1.58 (3 H,m), 2.50 (1 H, br. s.), 2.58 (1 H, s), 5.26- 5.91 (1 H, m) n/a T4-I.4

1,1,1-trifluoro-2-methylbut- 3-yn-2-ol (250 MHz, CDCl₃) δ 1.66 (3 H, s),2.62 (1 H, s), 2.77 (1 H, br. s.) n/a T4-I.5

3-ethynyl-3-hydroxy-1- methylpyrrolidin-2-one (500 MHz, CDCl3) delta ppm2.29 (dt, J = 12.85, 8.24 Hz, 1 H) 2.54 (td, J = 6.46, 2.84 Hz, 1 H)2.57 (s, 1 H) 2.93 (s, 3 H) 3.32-3.38 (m, 1 H) 3.39-3.47 (m, 1 H) 3.72(br. s., 1 H) 140 T4-I.6

2-(pyrazin-2-yl)but-3-yn- 2-ol (500 MHz, CDCl₃) delta 1.87 (3 H, s),2.65 (1 H, s), 4.45 (1 H, s), 8.51-8.56 (1 H, m), 8.59 (1 H, d, J = 2.52Hz), 8.99 (1 H, d, J = 1.42 Hz) 148.9 T4-I.7

2-(3-methyl-1,2-oxazol- 5-yl)but-3-yn-2-ol n/a T4-I.8

2-(pyrimidin-2-yl)but-3- yn-2-ol (250 MHz, CDCl₃) delta 1.92 (3 H, s),2.56 (1 H, s), 5.15 (1 H, s), 7.32 (1 H, t, J = 4.95 Hz), 8.82 (2 H, d,J = 4.87 Hz) 148.9 T4-I.9

4-ethynyl-1-methylpiperidin- 4-ol (250 MHz, CDCl₃) delta 2.08-1.74 (4 H,m), 2.27 (3 H, s), 2.43-2.30 (2 H, m), 2.48 (1 H, s), 2.75- 2.56 (2 H,m), 3.49 (1 H, s). 139.9 T4-I.10

2-(1H-pyrazol-3-yl)but- 3-yn-2-ol n/a 136.9 T4-I.11

2-(5-methyl-1,2,4-oxadiazol- 3-yl)but-3-yn-2-ol (500 MHz, CDCl₃) delta1.94 (3 H, s), 2.64 (3 H, s), 2.67 (1 H, s), 3.29 (1 H, br. s.) 152.9T4-I.12

2-(1H-imidazol-4-yl)but- 3-yn-2-ol n/a 136.9 T4-I.13

7-ethynyl-5H,6H-pyrrolo [1,2-c]imidazol-7-ol (250 MHz, DMSO) delta3.07-2.59 (2 H, m), 3.57 (1 H, s), 4.31-3.92 (2 H, m), 6.26 (1 H, s),6.77 (1 H, s), 7.52 (1 H, s). 148.9 T4-I.14

2-(3-methyl-1,2,4-oxadiazol- 5-yl)but-3-yn-2-ol (250 MHz, CDCl₃) delta1.96 (3 H, s), 2.44 (3 H, s), 2.72 (1 H, s), 3.39 (1 H, s). 152.9T4-I.15

1-fluoro-2-methylbut-3- yn-2-ol (500 MHz, CDCl₃) delta 1.62-1.66 (3 H,m), 2.53 (1 H, s), 3.49-3.56 (1 H, m), 3.60-3.65 (1 H, m) — T4-I.16

1-fluoro-2-(fluoromethyl) but-3-yn-2-ol (500 MHz, CDCl₃) delta ppm 3.64(1 H, s), 4.41- 4.64 (4 H, m) — T4-I.17

2-cyclopropylbut-3-yn- 2-ol (500 MHz, MeOD) delta 0.33-0.52 (3 H, m),0.54- 0.69 (1 H, m), 0.96-1.12 (1 H, m), 1.50 (3 H, s), 2.71 (1 H, s) —T4-I.18

1-cyclopropyl-2-methylbut- 3-yn-2-ol (250 MHz, CDCl₃) delta 2.36-2.51 (2H, m), 1.74 (1 H, dd, J = 13.9, 6.1 Hz), 1.44-1.58 (4 H, m), 0.79- 1.06(1 H,m), 0.40-0.66 (2 H, m), 0.03-0.29 (2 H, m) T4-I.19

3-ethynyloxetan-3-ol (400 MHz, CDCl₃): delta 2.73 (s, 1H), 3.41 (s, 1H),4.70 (d, J = 7.2 Hz, 2H), 4.85 (d, J = 7.2 Hz, 2H). T4-I.20

3-ethynyl-3- hydroxycyclobutanecarbonitrile T4-I.21

2-(1H-pyrazol-4-yl)but- 3-yn-2-ol (500 MHz, DMSO) delta 1.63 (3 H, s),3.35 (1 H, s), 5.74 (1 H, s), 7.46 (1 H, s), 7.62 (1 H, s), 12.64 (1 H,br. s.) 136.9 T4-I.22

7-ethynyl-5H,6H-cyclopenta [b]pyridin-7-ol

Example 23 Preparation of intermediate compound2-(2-methoxybut-3-yn-2-yl)-1,3-thiazole (I.5)

To a solution of 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (1-1) (1.0 g, 6.33mmol) in DMF (15 mL) cooled to 0° C., was slowly added sodium hydride(60% oil dispersion) (0.30 g, 7.6 mmol). After stirring at 0° C. for 20min, methyl iodide (0.47 mL, 7.6 mmol) was added. The solution waswarmed to RT. The mixture was partition between EtOAc (50 mL) and water(20 mL). The organic layer was washed with water, dried (Na₂SO₄),filtered and concentrated in vacuo. Purification by flash chromatography(Isolute column, 20% EtOAc in heptane) gave the title compound as a paleyellow oil: ¹H NMR (250 MHz, CDCl₃) δ1.91 (3H, s), 2.78 (1H, s), 3.41(3H, s), 7.35 (1H, d, J=3.20 Hz), 7.80 (1H, d, J=3.20 Hz); LC-MS:m/z=+167.9 (M+H)+.

Example 24 Preparation of 2-(4-methyl-1,3-thiazol-2-yl)but-3-yn-2-ol

Step 1—Synthesis of 1-(4-methyl-1,3-thiazol-2-yl)ethan-1-one

To a solution of n-butyllithium (2.5M in hexane, 14.4 mL) maintainedunder nitrogen at −78° C. was added a solution of 4-methyl-1,3-thiazole(3 g, 30.26 mmol) in ether (20 mL). The reaction mixture was stirred at−78° C. for 20 min. N-Methoxy-N-methylacetamide (3.4 g, 32.97 mmol) wasthen added dropwise to the reaction mixture over 10 min. The resultingsolution was stirred at −78° C. for 2 hr and then quenched by theaddition of aqueous sodium bicarbonate (20 mL). The resulting solutionwas extracted with ether (3×50 mL). The combined organic layers weredried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified on a silica gel column with ethyl acetate/petroleum ether (1/5)to give 2.1 g (39%) of 1-(4-methyl-1,3-thiazol-2-yl)ethan-1-one as ayellow oil: ¹H NMR (300 MHz, CDCl₃) delta 7.25 (s, 1H), 2.71 (s, 3H),2.51 (s, 3H).

Step 2: Synthesis of 2-(4-methyl-1,3-thiazol-2-yl)but-3-yn-2-ol

To a stirred solution of ethynylmagnesium bromide (0.5 M in THF, 30.6mL, 15.30 mmol) maintained under nitrogen at −20° C. was added slowly asolution of 1-(4-methyl-1,3-thiazol-2-yl)ethan-1-one (1.8 g, 10.20 mmol,80%) in tetrahydrofuran (10 mL) over a period of 20 min. The resultingsolution was stirred for 3 hr at 20-30° C. and then quenched by theaddition of water (20 mL). The resulting mixture was extracted withethyl acetate (3×30 mL). The combined organic layers were dried overNa₂SO₄, filtered and concentrated in vacuo. The crude residue waspurified on a silica gel column eluted with ethyl acetate/petroleumether (1/6) to yield 0.5 g (26%) of the title compound as a yellowsolid: LC-MS: m/z=+168 (M+H)+.

Example 25 Preparation of 2-(5-fluoropyridin-2-yl)but-3-yn-2-ol

Step 1: Synthesis of2-(5-fluoropyridin-2-yl)-4-(trimethylsilyl)but-3-yn-2-ol

To a stirred solution of 2-bromo-5-fluoropyridine (1.76 g, 10.00 mmol)in ether (20 mL) maintained under nitrogen at −78° C. was added asolution of s-butyllithium (1.3M in hexane, 10 mL, 13.00 mmol) dropwise.The reaction mixture was then stirred at −78° C. for 1 hr and4-(trimethylsilyl)but-3-yn-2-one (1.54 g, 10.98 mmol) was added to thereaction mixture dropwise with stirring at −78° C. The resultingsolution was stirred at −78° C. for 2 hr and then quenched by theaddition of saturated ammonium chloride solution (5 mL) and water (10mL). The resulting solution was extracted with ethyl acetate (3×20 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified on a silica gelcolumn with ethyl acetate/petroleum ether (1:3) to give 1 g (42%) of thetitle compound as a yellow oil: LC-MS: m/z=+238 (M+H)⁺.

Step 2: Synthesis of 2-(5-fluoropyridin-2-yl)but-3-yn-2-ol

A solution of 2-(5-fluoropyridin-2-yl)-4-(trimethylsilyl)but-3-yn-2-ol(1 g, 4.21 mmol) and potassium fluoride (987 mg, 16.99 mmol) in methanol(10 mL) was stirred for 2 hr at 50° C. The resulting solution wasdiluted with ethyl acetate (20 mL) and the solid material was removed byfiltration. The filtrate was concentrated in vacuo to give 600 mg (86%)of the title compound as yellow oil: LC-MS: m/z=+166 (M+H)⁺.

Example 26 Preparation of 2-(1-methyl-1,2,4-triazol-3-yl)but-3-yn-2-ol

Step 1—Synthesis of 1-(1-methyl-1,2,4-triazol-3-yl)ethanone

The title compound was prepared according to methods described in Chem.Pharm. Bull. 41(7) 1226-1231 (1993) and Organic Syntheses, Coll. Vol. 6,p. 601 (1988); Vol. 56, p. 72 (1977); ¹H NMR (500 MHz, CDCl₃) delta 2.66(3H, s), 4.01 (3H, s), 8.11 (1H, s); LC-MS: m/z=+125.90 (M+H)+.

Step 2: Synthesis of 2-(1-methyl-1,2,4-triazol-3-yl)but-3-yn-2-ol

To a solution of ethynylmagnesium bromide (0.5M in THF, 4.32 mL, 2.16mmol) at 0° C. was added 1-(1-methyl-1,2,4-triazol-3-yl)ethanone (180mg, 1.44 mmol) in THF (5 mL) slowly. The reaction mixture was allowed towarm to RT and stirred for a further 1.5 hr. The reaction mixture wasquenched with saturated aqueous NH₄Cl solution (10 mL) and the organicswere removed in vacuo. The product was extracted into EtOAc (×2) and thecombined organics were dried (Na₂SO₄), filtered and concentrated invacuo. Purification by column chromatography eluting with 2-10% methanolin DCM afforded the title compound: ¹H NMR (500 MHz, CDCl₃) delta 1.93(3H, s), 2.62 (1H, s), 3.53 (1H, s), 3.93 (3H, s), 8.01 (1H, s); LC-MS:m/z=+152.0 (M+H)+.

Example 27 Preparation of 7-ethynyl-5H,6H-pyrrolo[1,2-a]imidazol-7-ol

Step 1—Synthesis of 5H,6H,7H-pyrrolo[1,2-a]imidazol-7-ol

To a solution of imidazole (2 mL, 30.26 mmol) and acetic acid (0.12 mL,2.12 mmol) in dry dioxane (20 mL) under N₂ was added acrolein (3.03 mL,45.39 mmol) in 1 portion and the resultant solution heated to reflux for4 hr. The reaction mixture was concentrated in vacuo and theyellow-brown residue was purified by column chromatography, (elutionwith 25% methanol in DCM) to give the title product; ¹H NMR (500 MHz,DMSO) delta 2.25 (1H, ddt, J=13.06, 7.90, 3.94, 3.94 Hz), 2.70-2.87 (1H,m), 3.85 (1H, ddd, J=10.72, 8.51, 4.26 Hz), 4.03 (1H, ddd, J=10.72,7.80, 6.23 Hz), 4.86 (1H, dd, J=7.09, 3.00 Hz), 5.58 (1H, br. s.), 6.94(1H, s), 7.06 (1H, d, J=0.95 Hz); LC-MS: m/z=+124.9 (M+H)+.

Step 2—Synthesis of 5H,6H-pyrrolo[1,2-a]imidazol-7-one

To a solution of 5H,6H,7H-pyrrolo[1,2-a]imidazol-7-ol (7.1 g, 57.2 mmol)in DCM (70 mL) was added MnO₂ (34.8 g, 400.3 mmol) portion wise. Thereaction mixture was stirred vigorously at RT for 3 days under N₂. Thereaction mixture was filtered through Celite and washed with DCM (200mL) and EtOAc (200 mL). The filtrate was concentrated in vacuo to givethe title compound as a yellow solid (4.04 g, 58% yield); ¹H NMR (500MHz, CDCl₃) delta 3.08-3.23 (2H, m), 4.39 (2H, t, J=5.83 Hz), 7.26 (1H,s), 7.56 (1H, s); LC-MS: m/z=+122.9 (M+H)+.

Step 3—Synthesis of 7-ethynyl-5H,6H-pyrrolo[1,2-a]imidazol-7-ol

To a solution of ethynylmagnesium bromide (0.5M in THF, 14.6 mL, 7.3mmol) at 0° C. was added 5H,6H-pyrrolo[1,2-a]imidazol-7-one (900 mg,4.86 mmol) in THF (10 mL) slowly. The reaction mixture was allowed towarm to RT and stirred for 1 hr. The reaction mixture was quenched withsaturated aqueous NH₄Cl solution (10 mL) and the organics were removedin vacuo. The product was extracted into EtOAc (10 mL×2) and thecombined organics were dried (Na₂SO₄), filtered and concentrated invacuo. Purification by column chromatography (Biotage), eluting with3-10% methanol in DCM afforded the title product; ¹H NMR (500 MHz,CDCl₃) delta 2.55 (1H, s), 2.96 (1H, ddd, J=13.24, 7.57, 4.26 Hz),3.03-3.12 (1H, m), 3.16-3.22 (1H, m), 4.01 (1H, ddd, J=10.56, 8.12, 4.33Hz), 4.15 (1H, ddd, J=10.52, 7.29, 6.62 Hz), 6.84 (1H, d, J=1.10 Hz),7.11 (1H, d, J=0.79 Hz); LC-MS: m/z=+136.9 (M+H)+.

Example 28 Preparation of 3-ethynyl-3-hydroxy-1-methylpiperidin-2-one

Step 1—Synthesis of 3-(benzyloxy)pyridin-2-ol

Pyridine-2,3-diol (38 g, 342.04 mmol) was added to a solution ofpotassium hydroxide (21 g, 374.26 mmol) in methanol (400 mL) in portionswhile maintaining the reaction temperature below 30° C. Benzyl bromide(64.4 g, 376.53 mmol) was then added dropwise with stirring to thereaction mixture at room temperature. The resulting solution was stirredat 40° C. for 5 hr then concentrated in vacuo. The residue was dilutedwith water (500 mL) and the mixture was extracted with ofdichloromethane (2×500 mL). The combined organic layer was dried overanhydrous sodium sulfate and concentrated in vacuo. Recrystallizationfrom ethanol afforded the title compound (30 g, 43%) as a white solid:¹H NMR (400 MHz, DMSO) delta 11.60 (s, 1H), 7.45-7.28 (m, 5H), 6.96-6.89(m, 2H), 6.10-6.06 (m, 1H), 5.01 (s, 2H).

Step 2—Synthesis of 3-(benzyloxy)-1-methyl-1H-pyridin-2-one

To a solution of 3-(benzyloxy)pyridin-2-ol (25 g, 123.00 mmol) andpotassium hydroxide (10 g, 178.22 mmol, 1.45 equiv) in dimethylsulfoxide(250 mL) maintained under nitrogen atmosphere was added methyl iodide(27 g, 190.14 mmol) dropwise with stirring. The resulting solution wasstirred overnight at room temperature then concentrated under vacuum.The residue was diluted with water (500 mL) then extracted withdichloromethane (2×400 mL). The combined organic layer was washed withwater (3×500 mL), dried over anhydrous sodium sulfate and concentratedunder vacuum to give the title compound (25 g, 93%) as a light brownoil: 1H NMR (400 MHz, DMSO) delta 7.44-7.32 (m, 5H), 7.29-7.27 (m, 1H),6.91-6.88 (m, 1H), 6.12-6.09 (m, 1H), 5.02 (s, 2H), 3.44 (s, 3H).

Step 3—Synthesis of 3-hydroxy-1-methyl-1H-pyridin-2-one

A mixture of 3-(benzyloxy)-1-methyl-1H-pyridin-2-one (23 g, 106.85 mmol)and 10% palladium on carbon (2.3 g) in methanol (250 mL) was stirredunder 1 atmosphere of hydrogen for 5 hr at room temperature. Thecatalyst was removed by filtration. The filtrate was concentrated invacuo to give the title compound (12 g (90%) as a purple solid: 1H NMR(400 MHz, DMSO) delta 8.96 (s, 1H), 7.15-7.13 (m, 1H), 6.70-6.68 (m,1H), 6.07 (t, J=7.0 Hz, 1H), 3.47 (s, 3H).

Step 4—Synthesis of 3-hydroxy-1-methylpiperidin-2-one

A mixture of 3-hydroxy-1-methyl-1H-pyridin-2-one (11.5 g, 91.91 mmol)and Ru/Al2O3 (2.5 g) in methanol (120 mL) was stirred under hydrogen (10bar) in a 250-mL pressure reactor for 48 hr at 50° C. The catalyst wasremoved by filtration and the filtrate was concentrated in vacuo to givethe title compound (11.3 g, 90%) as a brown oil: 1H NMR (400 MHz, DMSOdelta 3.85-3.82 (m, 1H), 3.28-3.18 (m, 2H), 2.79 (s, 3H), 1.98-1.92 (m,1H), 1.87-1.81 (m, 1H), 1.75-1.69 (m, 1H), 1.64-1.55 (m, 1H).

Step 5—Synthesis of 1-methylpiperidine-2,3-dione

To a solution of 3-hydroxy-1-methylpiperidin-2-one (1 g, 7.59 mmol) inacetone (50 mL) was added Jones-reagent (2 mL) dropwise at roomtemperature. The resulting solution was stirred for 10 min at roomtemperature. The solid material was removed by filtration. The filtratewas concentrated in vacuo at 30-40° C. The residue was dissolved in DCM(50 mL), dried over anhydrous sodium sulfate and concentrated in vacuoto afford the title compound (220 mg, 11%) which was used in next stepimmediately without further purification.

Step 6—Synthesis of 3-ethynyl-3-hydroxy-1-methylpiperidin-2-one

To a solution of ethynylmagnesium bromide (0.5M in tetrahydrofuran, 4mL, 2 mmol) maintained under nitrogen at −20° C. was added a solution of1-methylpiperidine-2,3-dione (220 mg, 0.87 mmol) in tetrahydrofuran (3mL) dropwise with stirring within 1 min. The reaction mixture wasstirred for 2 hr at room temperature and then quenched by the additionof saturated ammonium chloride solution (1 mL). The mixture was dilutedwith DCM (50 mL), dried over anhydrous sodium sulfate and concentratedunder vacuum. The crude residue was purified on a silica gel column,elution with ethyl acetate/petroleum ether (0:1-1:0) afforded the titlecompound (40 mg, 30%) as a brown oil: 1H NMR (400 MHz, CDCl₃) delta 4.23(s, 1H), 3.35-3.30 (m, 2H), 2.95 (s, 3H), 2.47 (s, 1H), 2.35-2.16 (m,2H), 1.97-1.90 (m, 2H). LC-MS m/z=+154 [M+H]+.

Example 29 Preparation of 2-(1,3-oxazol-4-yl)but-3-yn-2-ol

Step 1—Synthesis of 1-(1,3-oxazol-4-yl)ethanone

To a solution of methylmagnesium bromide (3M solution in Et2O, 8.86 mL,26.58 mmol) was added slowly a solution of 1,3-oxazole-4-carbonitrile(500 mg, 5.32 mmol) in anhydrous Et₂O (10 mL). After addition thereaction mixture was stirred at 40° C. for 3 hr. The reaction mixturewas cooled to ambient temperature, and of methanol (5 mL) was addeddropwise. The reaction mixture was stirred for 3 hr and then filtered.The filtrate was collected and silica (5 g) was added and the mixturestirred at room temperature for 3 hr. The silica was filtered off andthe volume reduced (removed methanol). EtOAc and water were added andthe organics were extracted (repeated with CHCl₃:isopropanol 3:1),washed with water and dried (Na₂SO₄), filtered and concentrated invacuo. The crude material was purified by column chromatography(Biotage) (Eluted with 2-8% methanol in DCM) to give the title compound;¹H NMR (250 MHz, CDCl₃) delta 2.56 (3H, s), 7.91 (1H, d, J=0.7 Hz), 8.25(1H, d, J=0.9 Hz); LC-MS: m/z=+112 (M+H)+.

Step 2-Synthesis of 2-(1,3-oxazol-4-yl)but-3-yn-2-ol

To a solution of n-butyllithium (2.5M in hexane, 1.03 mL, 2.57 mmol) inTHF (3 mL) at −78° C. was added dropwise ethynyl(trimethyl)silane (0.34mL, 2.38 mmol). The reaction was stirred at −78° C. for 10 minutes andthen 1-(1,3-oxazol-4-yl)ethanone (220 mg, 1.98 mmol) was added in moreTHF (2 mL). The reaction was stirred at −78° C. to RT for 1 hr. Themixture was then diluted with water and the volatiles removed. Theproduct was then extracted with EtOAc (2×15 mL) and the combinedorganics washed with water (2×5 mL) and dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude material was purified by columnchromatography (eluted with 2-13% methanol) to give the title compound;¹H NMR (500 MHz, CDCl₃) delta 1.85 (3H, s), 2.61 (1H, s), 2.92 (1H, s),7.71 (1H, s), 7.87 (1H, s).

Example 30 Preparation and Separation of 2-(pyrimidin-4-yl)but-3-yn-2-ol(30-1) and 2-(pyrimidin-4-yl)-4-(trimethylsilyl)but-3-yn-2-ol (30-2)

To a solution of n-butyllithium (2.5M in hexane, 2.1 ml, 5.32 mmol) inTHF (3 mL) at −78° C. was added dropwise ethynyl(trimethyl)silane (0.7mL, 4.91 mmol). The reaction was stirred at −78° C. for 10 minutes andthen 1-(pyrimidin-4-yl)ethanone (0.5 g, 4.09 mmol) was added in more THF(2 mL). The reaction was stirred at −78° C. to RT overnight. The mixturewas diluted with water and the volatiles removed in vacuo. The productwas then extracted with CHCl₃:IPA (2:1 ratio, 2×25 mL). The organicphase was washed with water (20 mL), brine (20 mL); dried over Na₂SO₄and the solvent removed in vacuo. Purification by column chromatography(Biotage), eluting with 0-100% EtOAc-heptane afforded2-(pyrimidin-4-yl)-4-(trimethylsilyl)but-3-yn-2-ol; ¹H NMR (500 MHz,CDCl₃) delta 0.19 (9H, s), 1.78 (3H, s), 4.65 (1H, s), 7.65 (1H, dd,J=5.20, 1.10 Hz), 8.79 (1H, d, J=5.36 Hz), 9.20 (1H, s); LC-MS: m/z=+221(M+H)+; and 2-(pyrimidin-4-yl)but-3-yn-2-ol; ¹H NMR (500 MHz, CDCl₃)delta 1.79 (3H, s), 2.62 (1H, s), 4.99 (1H, s), 7.67 (1H, dd, J=5.28,0.87 Hz), 8.77 (1H, d, J=5.36 Hz), 9.19 (1H, s); LC-MS: m/z=+148.95(M+H)+.

Example 31 Preparation of 7-ethynyl-5H,6H-cyclopenta[b]pyridin-7-ol

To a solution of n-butyllithium (2.5M in hexane, 19.5 ml, 48.75 mmol) inTHF (15 ml) at −78° C. was added dropwise ethynyl(trimethyl)silane (6.41ml, 45.06 mmol). The reaction was stirred at −78° C. for 20 minutes andthen a solution of 5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (5 g, 7.51mmol) in THF (25 mL) was added. The reaction mixture was stirred at −78°C. to RT for 4 hr. The mixture was then diluted with water and thevolatiles removed in vacuo. The product was extracted with CHCl₃:IPA(2:1 ratio, 3×30 ml) and the orunic phase was washed with water (30 mL),brine (30 nit); dried over Na₂SO₄, filtered and concentrated in vacuo.Purification by column chromatography (Biotage), eluting with 0-5%MeOH-DCM followed by another column chromatography purification with 30%EtOAc/heptanes gave the title compound; ¹H NMR (500 MHz, CDCl₃) 2.49(1H, ddd, J=13.44, 8.24, 6.07 Hz), 2.63-2.76 (2H, m), 2.90-3.02 (1H, m),3.03-3.13 (1H, m), 3.42 (1H, s), 7.22 (1H, dd, J=7.57, 4.89 Hz), 7.62(1H, d, J=7.57 Hz), 8.51 (1H, d, J=4.73 Hz); LC-MS: m/z=+159.9 (M+H)+.

Example 32 Preparation of 2-(pyridin-2-yl)but-3-yn-2-ol

The title compound was prepared using the method described for thepreparation of 7-ethynyl-5H,6H-cyclopenta[b]pyridin-7-ol, by replacing5,6-dihydro-7H-cyclopenta[b]pyridin-7-one with 2-acetylpyridine; ¹H NMR(500 MHz, CDCl₃) delta 1.80 (3H, s), 2.55 (1H, s), 5.50 (1H, s),7.20-7.32 (1H, m), 7.62 (1H, d, J=7.88 Hz), 7.78 (1H, td, J=7.72, 1.58Hz), 8.54 (1H, d, J=4.73 Hz); LC-MS: m/z=+147.9 (M+H)+.

Example 33 Preparation of 2-(5-methylpyrazin-2-yl)but-3-yn-2-ol

The title compound was prepared using the method described for thepreparation of 7-ethynyl-5H,6H-cyclopenta[b]pyridin-7-ol, by replacing5,6-dihydro-7H-cyclopenta[b]pyridin-7-one with1-(5-methylpyrazin-2-yl)ethanone; ¹H NMR (500 MHz, CDCl₃) delta 1.65(3H, s), 2.45 (3H, s), 4.32 (1H, s), 8.22 (1H, s), 8.77 (1H, s); LC-MS:m/z=+162.9 (M+H)+.

Example 34 Preparation of 2-ethynylbicyclo[2.2.1]heptan-2-ol

Step 1—Synthesis of 2-((trimethylsilyl)ethynyl)bicyclo[2.2.1]heptan-2-ol

Bicyclo[2.2.1]heptan-2-one (1.1 g, 10 mmol) in THF was treated withn-BuLi (6 mL, 2.5 M in n-hexane) at −78° C. for about 30 min.Ethynyltrimethylsilane (1.1 g, 11 mmol) was then added and the reactionmixture was stirred for 3 hr. Purification by gel chromatographyafforded the title compound (1.6 g); ¹H NMR (400 MHz, DMSO) delta 0.16(s, 9H), 1.15-1.44 (m, 4H), 1.64-1.67 (m, 1H), 1.88-1.93 (m, 2H),2.07-2.22 (m, 3H), 3.94 (s, 1H).

Step 2: Synthesis of 2-ethynylbicyclo[2.2.1]heptan-2-ol

2-((trimethylsilyl)ethynyl)bicyclo[2.2.1]heptan-2-ol (700 mg, 5.1 mmol)was dissolved in THF (25 mL) and treated with TBAF (2.7 g, 10.2 mmol) at0° C. for 30 min. Purification by gel chromatography afforded the titlecompound; ¹H NMR (400 MHz, DMSO) delta 1.15-1.44 (m, 4H), 1.64-1.67 (m,1H), 1.88-1.93 (m, 2H), 2.07-2.22 (m, 3H), 3.25 (s, 1H)

Example 35 Preparation of 3-ethynyltetrahydro-2H-pyran-3-ol

Step 1—Synthesis of 3-((trimethylsilyl)ethynyl)tetrahydro-2H-pyran-3-ol

A solution of dihydro-2H-pyran-3(4H)-one (200 mg, 2 mmol) in THF wastreated with n-BuLi (2 mL) at −78° C. for about 30 min.Ethynyltrimethylsilane (300 mg, 3 mmol) was then added and the reactionmixture was stirred for 3 hr. Purification by gel chromatographyafforded the title compound (200 mg, 50%); ¹H NMR (400 MHz, DMSO) delta0.15 (s, 9H), 1.52-1.55 (m, 1H), 1.62-1.67 (m, 1H), 1.80-1.88 (m, 1H),3.23-3.26 (m, 1H), 3.37-3.44 (m, 1H), 3.49-3.56 (m, 2H), 5.52 (s, 1H).

Step 2—Synthesis of 3-ethynyltetrahydro-2H-pyran-3-ol

The title compound was prepared by the procedure described in Example34, by substituting2-((trimethyl-silyl)ethynyl)bicyclo[2.2.1]heptan-2-ol with3-((trimethylsilyl)ethynyl)tetrahydro-2H-pyran-3-ol in Step 2.

Example 36 Preparation of3-(tert-butyl-dimethyl-silanyloxymethyl)-1-ethynyl-cyclobutanol (36-d1)and 1-[3-(tert-butyl-dimethyl-silanyloxy)-cyclobutyl]-prop-2-yn-1-ol(36-d2)

Step 1—Synthesis of 3-hydroxymethyl-cyclobutanol (36-a)

To a solution of 3-oxo-cyclobutanecarboxylic acid (5.0 g, 44 mmol) intetrahydrofuran (50 mL) was added slowly BH3S(CH3)2 (5.9 mL, 14.7 mmol)at −78° C. The solution was stirred overnight at room temperature. Thereaction mixture was then quenched with methanol and purified by flashchromatography (Isolute column) Elution with 5% methanol in DCM affordedthe title compound; (3.4 g, 76%).

Step 2—Synthesis of3-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutanol (36-b1) and[3-(tert-butyl-dimethyl-silanyloxy)-cyclobutyl]-methanol (36-b2)

To a solution of 3-hydroxymethyl-cyclobutanol (0.4 g, 4 mmol) in DCM (20mL) was added triethylamine (1.2 g, 12 mmol) andtert-butyl-chloro-dimethyl-silane (1.2 g, 8 mmol). The solution wasstirred overnight at room temperature. The reaction mixture was thenwashed with water (×3) and the organic layers concentrated in vacuo. Thecrude residue was purified by flash chromatography to afford a mixtureof 3-(tert-butyl-dimethyl-silanyloxymethyl)cyclobutanol and[3-(tert-butyl-dimethyl-silanyloxy)-cyclobutyl]-methanol (0.6 g, 69%).

Step 3—Synthesis of3-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutanone (36-c1) and3-(tert-butyl-dimethyl-silanyloxy)-cyclobutanecarbaldehyde (36-c2)

To a mixture of 3-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutanol(36-b1) and [3-(tert-butyl-dimethyl-silanyloxy)-cyclobutyl]-methanol(36-b2) (0.5 g, 2.31 mmol) in DCM (10 mL) was added Dess-Martin reagent(1.47 g, 3.5 mmol). The reaction mixture was stirred for 3 hr at roomtemperature and then washed with water. The crude residue was purifiedby flash chromatography (Isolute column), elution with 5% petroleumether in EtOAc afforded a mixture of3-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutanone (36-c1) and3-(tert-butyl-dimethyl-silanyloxy)-cyclobutanecarbaldehyde (36-c2),(0.44 g, 89%).

Step 4—Synthesis of3-(tert-butyl-dimethyl-silanyloxymethyl)-1-ethynyl-cyclobutanol (36-d1)and 1-[3-(tert-butyl-dimethyl-silanyloxy)-cyclobutyl]-prop-2-yn-1-ol(36-d2)

To a mixture of 3-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutanone(36-c1) and 3-(tert-butyl-dimethyl-silanyloxy)-cyclobutanecarbaldehyde(36-c2) (0.44 g, 2.2 mmol) in tetrahydrofuran (20 mL) was added ethynylmagnesium bromide (6.7 mL, 3.3 mmol) at −78° C. The solution was stirredfor 5 hr at room temperature and then quenched with saturated aqueousNH₄Cl solution. The product was extracted with DCM and the organicsdried (Na₂SO₄), filtered and concentrated in vacuo to afford a mixtureof 3-(tert-butyl-dimethyl-silanyloxymethyl)-1-ethynyl-cyclobutanol and1-[3-(tert-butyl-dimethyl-silanyloxy)-cyclobutyl]-prop-2-yn-1-ol (0.41g, 78%).

Example 37 Preparation oftert-butyl-(2,2-dimethyl-but-3-ynyloxy)-dimethyl-silane

Step 1—Synthesis of3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propan-1-ol

To a solution of 2,2-dimethyl-propane-1,3-diol (5.0 g, 48 mmol) in DCM(20 mL) was added triethylamine (14.6 g, 144.3 mmol) andtert-butyl-chloro-dimethyl-silane (7.2 g, 48.1 mmol). The solution wasstirred overnight at room temperature. The reaction mixture was thenwashed with water (×3) and concentrated in vacuo. The residue waspurified by flash chromatography to afford the title compound (6.1 g,58%): ¹H NMR (CDCl₃, 400 MHz) delta 0.04 (s, 6H), 0.86 (s, 6H), 0.87 (s,9H), 2.94 (s, 1H), 3.43 (s, 4H).

Step 2—Synthesis of3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propionaldehyde

To a solution of3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propan-1-ol (3.0 g, 13.8mmol) in DCM (30 ml) was added Dess-Martin reagent (8.6 g, 20.6 mmol)and the reaction mixture was stirred overnight at room temperature. Thereaction mixture was then washed with water and concentrated in vacuo.The crude residue was purified by flash chromatography (eluted withpetroleum ether: EtOAc=100:1) to afford the title compound (1.6 g, 54%):¹H NMR (CDCl₃, 400 MHz) delta 0.05 (s, 6H), 0.88 (s, 9H), 1.17 (s, 6H),3.59 (s, 2H).

Step 3—Synthesis oftert-butyl-(2,2-dimethyl-but-3-ynyloxy)-dimethyl-silane

To a solution of3-(tert-butyl-dimethyl-silanyloxy)-2,2-dimethyl-propionaldehyde (0.84 g,3.9 mmol) in methanol (20 mL) was added(1-diazo-2-oxo-propyl)-phosphonic acid dimethyl ester (0.9 g, 4.7 mmol)and K₂CO₃ (1.1 g, 7.8 mmol). The solution was stirred overnight at roomtemperature and then the reaction mixture was washed with water. Thecrude residue was purified by flash chromatography (eluted with:petroleum ether: EtOAc=100:2) to afford the title compound (0.17 g,21%): ¹H NMR (CDCl₃, 400 MHz) delta 0.05 (s, 6H), 0.90 (s, 9H), 1.19 (s,6H), 2.06 (s, 1H), 3.45 (s, 2H).

Example 38 Preparation oftert-butyl-(1-ethynyl-cyclopentylmethoxy)-dimethylsilane

Step 1—Synthesis of[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclopentyl]-methanol

(1-hydroxymethyl-cyclopentyl)-methanol (1.0 g, 7.7 mmol) was dissolvedin DCM (30 ml) and TEA (1.15 g, 7.7 mmol) and DMAP (0.14 g, 1.15 mmol)were added. TBSCl (1.17 g, 11.5 mmol) was then added in portions and themixture was stirred at room temperature for 16 hr. The reaction mixturewas washed with saturated aqueous NaHCO₃ solution and extracted withEtOAc. The organic phase was concentrated and the crude residue waspurified by chromatography on silica gel (eluted with hexanes:EtOAc,10:1) to afford the title compound (1.1 g, yield 59%): ¹H NMR (400 MHz,DMSO) delta 0.00 (s, 6H), 0.84 (s, 9H), 1.28-1.31 (m, 4H), 1.46-1.50 (m,4H), 3.20 (d, J=5.2 Hz, 2H), 3.36 (s, 2H), 4.38 (t, J=5.2 Hz, 1H).

Step 2—Synthesis of1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclopentanecarbaldehyde

[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclopentyl]-methanol (1.1 g,4.51 mmol) was dissolved in DCM (30 ml) and Dess-Martin reagent (3.82 g,9.0 mmol) was added in portions. The reaction mixture was stirred atroom temperature for 4 hr and filtered. The filtrate was concentrated invacuo and purified by silica gel chromatography (eluted withhexanes:EtOAc, 10:1) to afford the title compound (0.75 g, 64%): ¹H NMR(400 MHz, DMSO) delta 0.00 (s, 6H), 0.84 (s, 9H), 1.28-1.31 (m, 4H),1.46-1.50 (m, 4H), 3.76 (s, 2H), 9.54 (s, 1H).

Step 3—Synthesis of (1-diazo-2-oxo-propyl)-phosphonic acid dimethylester

(2-oxo-propyl)-phosphonic acid dimethyl ester (20 g, 0.12 mol) wasdissolved in toluene (500 mL) at 0° C. and NaH (4.8 g, 0.12 mol) wasadded in portions. After the gas evolution had ceased, a solution of4-methyl-benzenesulfonyl azide (21.4 g, 1.1 mol) was added drop-wise andthe mixture was stirred at room temperature for 16 hr. The mixture wasdiluted with hexanes, filtered through a pad of celite and rinsed withTMBE. The filtrate was concentrated to afford the title compound (16 g,70%): ¹H NMR (400 MHz, DMSO) delta 2.22 (s, 3H), 3.74 (s, 3H), 3.79 (s,3H).

Step 4—Synthesis oftert-butyl-(1-ethynyl-cyclopentylmethoxy)-dimethylsilane

To a mixture of1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclopentanecarbaldehyde (750mg, 3.1 mmol) in methanol (20 mL) was added K₂CO₃ (855 mg, 6.2 mmol)followed by dropwise addition of (1-diazo-2-oxo-propyl)-phosphonic aciddimethyl ester (714 mg, 3.6 mmol). The mixture was stirred at roomtemperature for 4 hr and then diluted with TMBE and washed with NaHCO₃.The product was extracted with EtOAc and the organic phase wasconcentrated and purified by flash chromatography to afford the titlecompound (400 mg, 54.2%): ¹H NMR (400 MHz, DMSO) delta 0.00 (s, 6H),0.83 (s, 9H), 1.53-1.64 (m, 8H), 2.82 (s, 1H), 3.44 (s, 2H).

Example 39 Preparation of 2-methyl-1-(1H-pyrazol-1-yl)but-3-yn-2-ol

Step 1—Synthesis of 1-(1H-pyrazol-1-yl)propan-2-one

1H-pyrazole (1.0 g, 15 mmol) was dissolved in chloroacetone (3.0 g, 32mmol) and heated at 90° C. for 10 hr. Purification by silica gel column,elution with 1:1 hexanes:DCM afforded the title compound (700 mg): ¹HNMR (400 MHz DMSO) delta 2.05 (s, 3H), 5.09 (s, 2H), 6.29 (t, J=2.0 Hz,1H), 7.47 (dd, J=0.4, 1.6 Hz, 1H), 7.67 (dd, J=0.4, 2.0 Hz, 1H).

Step 2—Synthesis of 2-methyl-1-(1H-pyrazol-1-yl)but-3-yn-2-ol

The title compound was prepared by procedure described in Example 22(T4-119), by substituting oxetan-3-one with1-(1H-pyrazol-1-yl)propan-2-one (39-a). Purification by gelchromatography afforded 2-methyl-1-(1H-pyrazol-1-yl)but-3-yn-2-ol (yield28%).

Example 40 Preparation of1-(tert-butyl-dimethyl-silanyloxy)-2-methyl-but-3-yn-2-ol

1-(tert-butyl-dimethyl-silanyloxy)-propan-2-one (500 mg, 2.6 mmol) wasdissolved in THF (20 mL) and treated with ethynylmagnesium bromide (0.5M, 8 mL) for 10 hr. The solution was extracted with EtOAc, and theorganic layer was dried over Na₂SO₄ and concentrated in vacuo to affordthe title compound (380 mg, 68.3%): ¹H NMR (400 MHz DMSO) delta 0.10 (s,6H), 0.92 (s, 9H), 1.40 (s, 3H), 2.74 (s, 1H), 3.58 (d, J=9.6 Hz, 1H),3.61 (d, J=9.6 Hz, 1H).

Example 41 Preparation of2-[5-(hydroxymethyl)isoxazol-3-yl]but-3-yn-2-ol

To a solution of ethynylmagnesium bromide (0.5M in THF, 99 mL, 49.0mmol) at 0° C. under N2 was added a solution of1-[5-(hydroxymethyl)isoxazol-3-yl]ethanone (prepared according toSynthesis 2005, 20, 3541) (4.10 g, 29.0 mmol) in dry THF (25 mL) over 20minutes. The reaction mixture was warmed to RT for 1.5 hr, quenched bydropwise addition of saturated aqueous ammonium chloride (20 mL) andconcentrated in vacuo. After re-dissolving the residue in EtOAc (100mL), the aqueous phase was removed, diluted with water to dissolve allsuspended solids and washed with EtOAc (100 mL). The combined organicextracts were dried (Na₂SO₄), filtered and concentrated in vacuo tofurnish the crude title compound as a red-brown syrup: ¹H NMR (500 MHz,CDCl₃) delta 1.88 (3H, s), 2.67 (1H, s), 4.77 (2H, s), 6.39 (1H, s);LC-MS: m/z=+167.9 (M+H)+. This compound, with LC-MS purity=88% UV, wasused in the next step without further purification.

Example 42 Preparation of 2-[5-(fluoromethyl)isoxazol-3-yl]but-3-yn-2-ol

Step 1—Synthesis of [3-(2-hydroxybut-3-yn-2-yl)isoxazol-5-yl]methyl4-methylbenzenesulfonate

To a solution of 2-[5-(hydroxymethyl)isoxazol-3-yl]but-3-yn-2-ol (500mg, 2.99 mmol) in DCM (5 mL) at 0° C. under an atmosphere of nitrogenwas introduced triethylamine (333 mg, 3.29 mmol) and p-toluenesulfonylchloride (627 mg, 3.29 mmol) in one portion. After warming to RT for 3hr, the reaction mixture was diluted with DCM (10 mL) and washed withbrine (5 mL). The organic extract was dried (Na₂SO₄), filtered and thefiltrate adsorbed onto silica gel in vacuo. Purification by silica gelflash column chromatography (heptane/EtOAc gradient of increasingpolarity) furnished the title compound as a colorless oil: ¹H NMR (500MHz, CDCl₃) delta 1.84 (3H, s), 2.26 (3H, s), 2.66 (1H, s), 2.86 (1H,br. s), 5.14 (2H, s), 6.41 (1H, s), 7.36 (2H, d, J=8.1 Hz), 7.80 (2H, d,J=8.1 Hz); LC-MS: m/z=+321.9 (M+H)+.

Step 2—Synthesis of 2-[5-(fluoromethyl)isoxazol-3-yl]but-3-yn-2-ol

To a solution of [3-(2-hydroxybut-3-yn-2-yl)isoxazol-5-yl]methyl4-methylbenzenesulfonate (259 mg, 0.81 mmol) in dry acetonitrile (10 mL)was introduced potassium fluoride (94 mg, 1.61 mmol) and Kryptopfix® 222(606 mg, 1.61 mmol). After 5 hr rapid stirring at RT, the reactionmixture was concentrated in vacuo and the residue partitioned betweenEtOAc (40 mL) and water (2×40 mL). The organic extract was washed withbrine (30 mL), dried (Na₂SO₄), filtered and the filtrate adsorbed ontosilica gel in vacuo. Purification by silica gel flash columnchromatography (heptane/EtOAc gradient of increasing polarity) furnishedthe title compound as a colorless oil: ¹H NMR (500 MHz, CDCl₃) delta1.91 (3H, s), 2.69 (1H, s), 2.86 (1H, s), 5.42 (1H, d, J=47.3 Hz), 6.55(1H, d, J=2.8 Hz); ¹⁹F NMR—decoupled (235 MHz, CDCl₃) delta −218.8 (s);LC-MS: m/z=+169.9 (M+H)+.

Example 43 Preparation of 2-hydroxy-N,N,2-trimethylbut-3-ynamide

Step 1—Synthesis of N,N-dimethyl-2-oxopropanamide

To a solution of pyruvoyl chloride (3.28 g, 30.80 mmol) in dry DCM (25mL) at 0° C. under an atmosphere of nitrogen was introduced a pre-mixedsolution of dimethylamine (18 mL of a 2M solution in THF, 36.00 mmol)and triethylamine (5.0 mL, 35.94 mmol) dropwise over 10 min. After 1 hrat this temperature, the reaction mixture was diluted with DCM (50 mL),washed with hydrochloric acid (3×20 ml 1.0M HCl aq.), brine (20 ml) anddried (Na₂SO₄). Following filtration, the filtrate was concentrated invacuo to furnish the crude title compound as an orange-brown oil: ¹H NMR(500 MHz, CDCl₃) delta 2.44 (3H, s), 3.00 (3H, s), 3.03 (3H, s). Thiscompound, estimated as 90%+ purity by ¹H NMR, was used in the next stepwithout further purification.

Step 2—Synthesis of 2-hydroxy-N,N,2-trimethylbut-3-ynamide

To a solution of N,N-dimethyl-2-oxopropanamide (413 mg, 3.59 mmol) indry THF (10 mL) at 0° C. under an atmosphere of nitrogen was introducedethynylmagnesium bromide (10 mL of a 0.5M solution in THF, 5.00 mmol)dropwise over 10 minutes. After warming to RT for 1 hr, water wasintroduced dropwise until gas evolution ceased and the resulting slurryconcentrated in vacuo. The residue was slurried in DCM (50 mL) withsonication for 5 min. and the mixture filtered. Following re-suspensionof the filter cake in water (10 mL), the pH was adjusted to 2 with 1Maqueous hydrochloric acid and the resulting hazy solution re-extractedwith DCM (30 mL). The DCM extract was combined with the DCM filtrate,dried (Na₂SO₄), filtered and the filtrate concentrated in vacuo tofurnish the crude title compound as a brown oil: ¹H NMR (500 MHz, CDCl₃)delta 1.68 (3H, s), 2.64 (1H, s), 3.08 (3H, s), 3.31 (3H, s), 5.25 (1H,br. s); LC-MS: m/z=+141.95 (M+H)+.

Example 44 Preparation of2-[5-(methoxymethyl)isoxazol-3-yl]but-3-yn-2-ol

Step 1—Synthesis of 1-[5-(methoxymethyl)isoxazol-3-yl]ethanone

To a solution of 1-[5-(hydroxymethyl)-1,2-oxazol-3-yl]ethanone (1.00 g,7.09 mmol) in dry THF (20 mL) under an atmosphere of nitrogen wasintroduced cesium carbonate (2.31 g, 7.09 mmol) and methyl iodide (5.03g, 35.43 mmol). The reaction mixture was warmed to 60° C. for 16 hr,cooled to RT and the solids removed by filtration. The filtrate wasre-treated with additional cesium carbonate (4.31 g, 13.23 mmol) andmethyl iodide (9.59 g, 67.58 mmol) and warmed to 60° C. for 34 hr. Aftercooling to RT, the reaction mixture was filtered, concentrated in vacuoand the residue re-dissolved in EtOAc (50 mL). The EtOAc solution waswashed with water (25 mL), brine (25 mL), dried (Na₂SO₄) and filtered.After concentrating the filtrate in vacuo, the residual oil was purifiedby silica gel flash column chromatography (95:5-50:50 gradient ofheptane/EtOAc) to furnish the title compound as a colorless oil: ¹H NMR(500 MHz, CDCl₃) delta 2.66 (3H, s), 3.44 (3H, s), 4.59 (2H, s), 6.64(1H, s).

Step 2—Synthesis of 2-[5-(methoxymethyl)isoxazol-3-yl]but-3-yn-2-ol

To a solution of 1-[5-(methoxymethyl)isoxazol-3-yl]ethanone (220 mg,1.42 mmol) in dry THF (4 mL) at 0° C. under an atmosphere of nitrogen,was introduced ethynylmagnesium bromide (4.4 mL of a 0.5M solution inTHF, 2.20 mmol) dropwise over 5 min. After 1.5 hr at this temperature,the reaction was carefully quenched with water (0.2 mL) and theresulting suspension concentrated in vacuo. The residual syrup wasslurried in water (5 mL) and the pH adjusted to 2 with 5M aqueoushydrochloric acid for 5 min., then saturated sodium bicarbonate solutionintroduced until the pH was 7.5. Following extraction of the basicaqueous solution with EtOAc (2×100 ml), the combined EtOAc extracts weredried (Na₂SO₄), filtered and the filtrate concentrated in vacuo tofurnish the crude title compound as a pale brown oil: ¹H NMR (500 MHz,CDCl₃) delta 1.89 (3H, s), 2.66 (1H, s), 3.02 (1H, br. s), 3.45 (3H, s),4.55 (2H, s), 6.39 (1H, s); LC-MS: m/z=+181.95 (M+H)+.

Examples 45 (i) and 45 (ii) Preparation of(2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol [Example 45 (i)] and(2S)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol [Example 45 (ii)]

Step 1—Synthesis of 1-(5-methylisoxazol-3-yl)ethanone (1-a)

Ethyl nitrite gas was generated in situ by addition of a solution ofsodium nitrite (100 g, 1.44 mol) in 50 mL of ethanol and 400 mL of waterdropwise into a solution of 50 mL of concentrated sulfuric acid in 50 mLof ethanol and 400 mL of water in a stand-alone reaction vessel. Theethyl nitrite gas generated was bubbled into another reaction flaskcontaining a mixture of hexane-2,5-dione (80 g, 700.88 mmol) inconcentrated hydrochloric acid (10 mL). The resulting solution wasstirred for 6 hr at 50° C. After cooling to room temperature, thereaction mixture was diluted with ether (600 mL) then washed with ofsaturated sodium carbonate solution (2×500 mL) and brine (500 mL). Theorganic layer was dried with anhydrous sodium sulphate then concentratedin vacuo. The crude product was purified by distillation under reducedpressure (12 mm Hg) and the fraction with the boiling point of 70° C.was collected to give 61 g (69%) of the title compound as a colorlessliquid: ¹H NMR (300 MHz, CDCl₃) delta 6.36 (s, 1H), 2.63 (s, 3H), 2.49(s, 3H).

Step 2—Synthesis of 2-(5-methylisoxazol-3-yl)but-3-yn-2-ol

To a stirred solution of ethynylmagnesium bromide (0.5 M in THF, 50 mL,25 mmol) maintained under nitrogen below 0° C. was added a solution of1-(5-methyl-1,2-oxazol-3-yl)ethan-1-one (2.5 g, 19.98 mmol) intetrahydrofuran (20 mL) dropwise over 5 min. The resulting solution waswarmed to room temperature and then stirred for a further 3 hr. Thereaction was quenched by the addition of saturated ammonium chloridesolution (100 mL) then extracted with ethyl acetate (2×100 mL). Thecombined organic layers was washed with brine (200 mL), dried withanhydrous sodium sulphate and concentrated in vacuo. The residue waspurified on a silica gel column, elution with ethyl acetate/petroleumether (0:1-1:4) afforded the title compound (2.3 g, 75%) as a colorlessoil: ¹H NMR (300 MHz, CDCl₃) delta 6.12 (s, 1H), 3.47 (s, 1H), 2.63 (s,1H), 2.42 (s, 3H), 1.86 (s, 3H).

Step 3—Chiral separation of(2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol and(2S)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

The racemic mixture of (45-b) was separated on preparative chiral columnby the method described in WO 2009/158011 to give(2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol and(2S)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol.

Examples 46 (i) and 46 (ii) Preparation of(2R)-2-(1,3-thiazol-2-yl)but-3-yn-2-ol [Examples 46 (i)] and(2S)-2-(1,3-thiazol-2-yl)but-3-yn-2-ol [Examples 46 (ii)]

Step 1—Chiral separation of (2R)-2-(1,3-thiazol-2-yl)but-3-yn-2-ol and(2S)-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

The racemic mixture was separated on preparative chiral column by themethod described in WO 2009/158011 to give(2R)-2-(1,3-thiazol-2-yl)but-3-yn-2-ol and(2S)-2-(1,3-thiazol-2-yl)but-3-yn-2-ol.

Example 47 Preparation of(2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol [Example 47 (i)] and(2S)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol [Example 47 (ii)]

Step 1—Synthesis of 1-(5-methyl-1,2,4-oxadiazol-3-yl)ethanone

A mixture of acetonitrile (8.1 L), acetone (522.0 g, 9.0 mol) and iron(III) nitrate (727.2 g, 1.8 mol) was stirred under reflux for 16 h. Thesuspension was filtered through a pad of celite and the pad was washedwith DCM. The combined filtrates were concentrated to dryness. Theresidue was distilled at 80-110° C. at 13 mm to afford 80 g of crudeproduct. Flash column with DCM, followed by re-distillation at 100-109°C. at 13 mm afforded the title compound (54 g, 8%); ¹H NMR (CDCl₃, 400MHz): delta 2.63 (s, 6H); LC-MS: m/z=+126 (M+H)+.

Step 2—Synthesis of 2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

To a solution of ethynylmagnesium bromide (0.5 M in THF, 800 mL, 400mmol) at 0° C. was added 1-(5-methyl-1,2,4-oxadiazol-3-yl)ethanone (33.5g, 266 mmol) in THF (533 mL) slowly. The reaction was allowed to warm toroom temperature and stirred for 5 hours. After being quenched withsaturated NH₄Cl (750 mL) at 0° C., the THF was removed in vacuo and theaqueous residue was extracted with ethyl acetate (600 mL×2). Thecombined organic extracts were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to give dark brown oil. The darkbrown oil was purified by silica gel column chromatography use 10% ofethyl acetate in hexanes as eluent to give the title compound (36 g,89%), ¹H NMR (CDCl₃, 400 MHz): delta 3.93 (s, 1H), 2.63 (s, 1H), 2.61(s, 3H), 1.91 (s, 3H).

Step 3—Chiral separation of(2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol [Example 47 (i)] and(2S)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol [Example 47 (ii)]

The racemic mixture of 2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol(161 g) was separated by preparative SFC using the following conditionsto give the first eluting compound, [Example 47 (i)] (51.3 g, >95%chiral purity) and second eluting compound [Example 47 (ii)] (54.1g, >95% chiral purity). Separation conditions: Instrument: Thar 200preparative SFC; Column: ChiralCel OZ-H, 250×30 mmI.D, Mobile phase: Afor CO2 and B for IPA; Gradient: B 10%; Flow rate: 100 mL/min; Backpressure: 100 bar; Column temperature: 38° C.; Wavelength: 210 nm;Cycletime: 2 min; Sample preparation: Compound was dissolved in Methanolto ˜50 mg/ml; Injection: 1 ml per injection.

Example 48 Preparation of (2R)-2-(pyrimidin-2-yl)but-3-yn-2-ol [Example48 (ii)] and (2S)-2-(pyrimidin-2-yl)but-3-yn-2-ol [Example 48 (i)]

Step 1—Synthesis of 2-(pyrimidin-2-yl)but-3-yn-2-ol

A solution of 1-(pyrimidin-2-yl)ethan-1-one (2.5 g, 20.47 mmol) intetrahydrofuran (60 mL) was added dropwise into a ethynylmagnesiumbromide (0.5 M in tetrahydrofuran, 60 mL, 30 mmol,) solution withstirring at room temperature under nitrogen atmosphere. The reactionmixture was stirred at room temperature for 1 hr and then quenched bythe addition of saturated aqueous ammonium chloride (200 mL). Theresulting solution was extracted with ethyl acetate (2×300 mL) and thecombined organic layers were washed with brine (300 mL), dried overanhydrous sodium sulphate and concentrated in vacuo. The residue waspurified on a silica gel column, elution with ethyl acetate/petroleumether (0:1-1:1) afforded 2-(pyrimidin-2-yl)but-3-yn-2-ol (1.5 g, 50%) asyellow oil. ¹H NMR (400 MHz, CDCl₃) delta 8.82 (d, J=4.4 Hz, 2H),7.33-7.29 (m, 1H), 5.1 (s, 1H), 2.56 (s, 1H), 1.93 (s, 3H); LC-MS:m/z=149 (M+H)+.

Chiral separation of (2R)-2-(pyrimidin-2-yl)but-3-yn-2-ol [Example 48(ii)] and (2S)-2-(pyrimidin-2-yl)but-3-yn-2-ol [Example 48 (i)]

The racemic mixture of 2-(pyrimidin-2-yl)but-3-yn-2-ol was separated bypreparative SFC using the following conditions to give the first elutingcompound (2S)-2-(pyrimidin-2-yl)but-3-yn-2-ol Example 48 (i) and secondeluting compound (2R)-2-(pyrimidin-2-yl)but-3-yn-2-ol [Example 48 (ii)].Separation conditions: Column: Chiralpak IC, 3×25 cm, 5 um column;Mobile phase A: CO2; Mobile phase B: Isopropanol (0.1% NH4OH); Isocraticcondition: 90% A/10% B; Flow rate: 200 mL/min; UV: 254 nm; Backpressure:120 Bar; Temp: 40 degrees C.

Example 49

Examples in Table 5 were prepared by procedure described in Example 5 byreacting 4-(6-bromo-3-methyl-1H-indazol-1-yl)pyrimidin-2-amine with theappropriate but-3-yn-2-ol intermediates.

TABLE 5 MS No. Structure Name 1H NMR (M + H) T5-49.1

(2R)-4-[1- (2- aminopyrimidin- 4-yl)- 3-methyl- 1H-indazol-6-yl]-2-(1,3- thiazol-2- yl)but-3-yn- 2-ol (500 MHz, DMSO) delta 1.94 (3H, s), 2.57 (3 H, s), 6.97 (2 H, br. s.), 7.04 (1 H, d, J = 5.36 Hz),7.08 (1 H, s), 7.34 (1 H, d, J = 8.20 Hz), 7.70 (1 H, d, J = 3.15 Hz),7.78 (1 H, d, J = 3.15 Hz), 7.84 (1 H, d, J = 8.20 Hz), 8.27 (1 H, br.s.), 8.85 (1 H, s) 377.35 T5-49-2

4-[1-(2- aminopyrimidin- 4-yl)-3- methyl-1H- indazol-6-yl]- 2-(3-methyl-1,2-oxazol- 5-yl)but-3- yn-2-ol (500 MHz, DMSO) delta 1.86 (3 H, s),2.25 (3 H, s), 2.58 (3 H, s), 6.45 (1 H, s), 6.76 (1 H, s), 6.99 (2 H,br. s.), 7.05 (1 H, s), 7.39 (1 H, d, J = 8.35 Hz), 7.87 (1 H, d, J =8.20 Hz), 8.27 (1 H, d, J = 5.36 Hz), 8.90 (1 H, s) 375.45 T5-49.3

(2S)-4-[1-(2- aminopyrimidin- 4-yl)- 3-methyl- 1H-indazol- 6-yl]-2-(1,3-thiazol-2- yl)but-3-yn- 2-ol (500 MHz, DMSO) delta 1.94 (3 H, s), 2.57(3 H, s), 6.98 (2 H, br. s.), 7.06 (1 H, br. s.), 7.08 (1 H, s), 7.34 (1H, d, J = 7.88 Hz), 7.70 (1 H, d, J = 2.36 Hz), 7.76-7.82 (1 H, m), 7.84(1 H, d, J = 8.20 Hz), 8.31 (1 H, br. s.), 8.85 (1 H, s) 377.1 T5-49.4

4-[1-(2- aminopyrimidin- 4-yl)-3- methyl-1H- indazol-6-yl]- 2-(4-methyl-1,3-thiazol- 2-yl)but-3- yn-2-ol (500 MHz, DMSO) delta 1.92 (3 H, s),2.37 (3 H, s), 2.58 (3 H, s), 6.97 (2 H, br. s.), 7.01 (1 H, s), 7.04 (1H, d, J = 5.36 Hz), 7.20-7.24 (1 H, m), 7.35 (1 H, d, J = 8.67 Hz), 7.85(1 H, d, J = 8.20 Hz), 8.26 (1 H, br. s.), 8.85 (1 H, s) 391.05 T5-49.5

4-[1-(2- aminopyrimidin- 4-yl)-3- methylindazol- 6-yl]-2-(5- methyl-1,3-thiazol-2-yl) but-3-yn- 2-ol (500 MHz, DMSO) delta 1.91 (3 H, s), 2.44(3 H, d, J = 1.10 Hz), 2.57 (3 H, s), 6.91-7.00 (3 H, m), 7.04 (1 H, d,J = 5.52 Hz), 7.34 (1 H, dd, J = 8.28, 1.18 Hz), 7.44 (1 H, d, J = 1.26Hz), 7.84 (1 H, d, J = 8.20 Hz), 8.26 (1 H, d, J = 5.52 Hz), 8.85 (1 H,s) 391.4 T5-49.6

4-[1-(2- aminopyrimidin- 4-yl)-3- methyl-1H- indazol-6-yl]- 2-(1,3-thiazol-5-yl)but- 3-yn-2-ol (500 MHz, DMSO) delta 1.93 (3 H, s), 2.58 (3H, s), 6.79 (1 H, s), 6.98 (2 H, br. s.), 7.04 (1 H, d, J = 5.52 Hz),7.40 (1 H, dd, J = 8.20, 1.10 Hz), 7.86 (1 H, d, J = 8.20 Hz), 8.00 (1H, s), 8.26 (1 H, d, J = 5.52 Hz), 8.90 (1 H, s), 9.03 (1 H, s) 377.35T5-49.7

4-[1-(2- aminopyrimidin- 4-yl)-3- methyl-1H- indazol-6-yl]- 2-(5-methyl-1,2,4-oxadiazol- 3-yl) but-3-yn-2-ol (500 MHz, DMSO) delta 1.90 (3 H,s), 2.58 (3 H, s), 2.63 (3 H, s), 6.76 (1 H, s), 6.97 (2 H, br. s.),7.04 (1 H, d, J = 5.52 Hz), 7.36 (1 H, dd, J = 8.20, 1.26 Hz), 7.86 (1H, d, J = 8.20 Hz), 8.26 (1 H, d, J = 5.52 Hz), 8.87 (1 H, s) 376.4T5-49.8

4-[1-(2- aminopyrimidin- 4-yl)-3- methyl-1H- indazol-6-yl]- 2-(5-methyl-1,2-oxazol- 3-yl)but-3- yn-2-ol (500 MHz, DMSO) delta 1.86 (3 H, s),2.42 (3 H, s), 2.57 (3 H, s), 6.41 (1 H, s), 6.55 (1 H, s), 6.97 (2 H,br. s.), 7.04 (1 H, d, J = 5.52 Hz), 7.35 (1 H, dd, J = 8.20, 1.26 Hz),7.85 (1 H, d, J = 8.20 Hz), 8.26 (1 H, d, J = 5.52 Hz), 8.86 (1 H, s)375.45 T5-49.9

4-[1-(2- aminopyrimidin- 4-yl)-3- methyl-1H- indazol-6-yl]- 2-(4-methyl-1,2,5- oxadiazol-3-yl) but-3-yn-2-ol (500 MHz, DMSO) delta 2.01 (3 H,s), 2.58 (3 H, s), 2.59 (3 H, s), 6.91 (1 H, s), 6.97 (2 H, br. s.),7.04 (1 H, d, J = 5.36 Hz), 7.39 (1 H, dd, J = 8.20, 1.10 Hz), 7.87 (1H, d, J = 8.20 Hz), 8.28 (1 H, s), 8.91 (1 H, s) 376.4 T5-49.10

4-[1-(2- aminopyrimidin- 4-yl)-3- methyl-1H- indazol-6-yl]- 2-(pyrazin-2-yl)but-3- yn-2-ol (500 MHz, DMSO) delta 1.91 (3 H, s), 2.57 (3 H, s),6.69 (1 H, s), 6.97 (2 H, br. s.), 7.04 (1 H, d, J = 5.36 Hz), 7.35 (1H, dd, J = 8.20, 1.26 Hz), 7.83 (1 H, d, J = 8.20 Hz), 8.26 (1 H, s),8.60-8.71 (2 H, m), 8.86 (1 H, s), 9.06 (1 H, s) 372.4 T5-49.11

4-[1-(2- aminopyrimidin- 4-yl)-3- methyl-1H- indazol-6-yl]-2-(pyrimidin- 2-yl)but- 3-yn-2-ol (500 MHz, DMSO) delta 1.92 (3 H, s),2.56 (3 H, s), 6.23 (1 H, s), 6.97 (2 H, br. s.), 7.03 (1 H, d, J = 5.52Hz), 7.30 (1 H, dd, J = 8.28, 1.18 Hz), 7.51 (1 H, t, J = 4.81 Hz), 7.82(1 H, d, J = 8.20 Hz), 8.25 (1 H, d, J = 5.52 Hz), 8.82 (1 H, s), 8.90(2 H, d, J = 4.89 Hz) 372.4 T5-49.12

4-{2-[1-(2- aminopyrimidin- 4-yl)- 3-methyl-1H- indazol- 6-yl]ethynyl}-1- methylpiperidin- 4-ol (500 MHz, DMSO) delta 1.82 (2 H, br. s.), 1.97(2 H, d, J = 12.61 Hz), 2.26 (3 H, br. s.), 2.32-2.69 (4 H, m), 2.57 (3H, s), 5.64 (1 H, br. s.), 6.96 (2 H, br. s.), 7.04 (1 H, d, J = 5.52Hz), 7.34 (1 H, dd, J = 8.20, 1.10 Hz), 7.83 (1 H, d, J = 8.20 Hz), 8.26(1 H, d, J = 5.52 Hz), 8.84 (1 H, s) 363.05 T5-49.13

4-[1-(2- aminopyrimidin- 4-yl)-3- methyl-1H- indazol-6-yl]-2-(1H-pyrazol- 3-yl)but- 3-yn-2-ol (250 MHz, DMSO) delta 1.88 (3 H, s),2.57 (3 H, s), 5.63 (1 H, s), 6.37 (1 H, d, J = 1.83 Hz), 6.51 (2 H, br.s.), 7.07 (1 H, d, J = 5.48 Hz), 7.32-7.40 (1 H, m), 7.51 (1 H, s), 7.78(1 H, d, J = 8.22 Hz), 8.25 (1 H, d, J = 5.63 Hz), 8.81 (1H, s) 360.05T5-49.14

4-[1-(2- aminopyrimidin- 4-yl)-3- methyl-1H- indazol-6-yl]-2-(1H-imidazol- 4-yl)but- 3-yn-2-ol (250 MHz, MeOD) delta 1.92 (3 H, s),2.60 (3 H, s), 7.20 (2 H, d, J = 5.63 Hz), 7.40 (1 H, d, J = 8.53 Hz),7.64-7.81 (2 H, m), 8.20 (1 H, d, J = 5.63 Hz), 9.00 (1 H, s) 360.05T5-49.15

4-[1-(2- aminopyrimidin- 4-yl)-3- methyl-1H- indazol-6-yl]- 2-[5-(hydroxymethyl)- 1,2-oxazol- 3-yl]but-3- yn-2-ol (500 MHz, DMSO) delta1.88 (3 H, s), 2.58 (3 H, s), 4.57 (2 H, d, J = 6.15 Hz), 5.68 (1 H, t,J = 6.07 Hz), 6.55 (1 H, s), 6.64 (1 H, s), 6.99 (2 H, br. s.), 7.04 (1H, d, J = 5.52 Hz), 7.36 (1 H, dd, J = 8.20, 1.26 Hz), 7.86 (1 H,d, J =8.20 Hz), 8.26 (1 H, d, J = 4.89 Hz), 8.87 (1 H, s) 391.4 T5-49.16

7-{2-[1-(2- aminopyrimidin- 4-yl)- 3-methyl-1H- indazol- 6-yl]ethynyl}-5H,6H,7H- pyrrolo [1,2-a] imidazol-7-ol (500 MHz, DMSO) delta 2.58 (3 H,s), 2.83 (1 H, d, J = 13.40 Hz), 3.12 (1 H, d, J = 13.24 Hz), 4.02-4.14(2 H, m), 6.57 (1 H, s), 7.00 (1 H, s), 6.98 (1 H, s), 7.04 (1 H, d, J =5.52 Hz), 7.15 (1 H, s), 7.37 (1 H, d, J = 8.20 Hz), 7.86 (1 H, d, J =8.35 Hz), 8.26 (1 H, d, J = 5.52 Hz), 8.89 (1 H, s) 372.05 T5-49.17

4-[1-(2- aminopyrimidin- 4-yl)-3- methyl-1H- indazol-6-yl]- 2-hydroxy-N,N,2- trimethylbut-3- ynamide (500 MHz, DMSO) delta 1.66 (3 H, s), 2.53(3 H, s), 2.87 (3 H, s), 3.33 (3 H, s), 7.04 (1 H, d, J = 5.67 Hz), 7.34(1 H, dd, J = 8.20, 0.95 Hz), 7.81 (1 H, d, J = 8.20 Hz), 8.22 (1 H, d,J = 5.36 Hz), 8.82 (1 H, s) 365.1 T5-49.18

4-[1-(2- aminopyrimidin- 4-yl)-3- methyl-1H- indazol-6-yl]- 1-fluoro-2-methylbut- 3-yn-2-ol (500 MHz, MeOD) delta 1.61 (3 H, d, J = 1.89 Hz),2.58 (3 H, s), 4.43 (2 H, dd, J = 47.29, 1.26 Hz), 5.49 (1 H, s), 7.20(1 H, d, J = 5.83 Hz), 7.36 (1 H, dd, J = 8.35, 1.26 Hz), 7.71 (1 H, dd,J = 8.20, 0.63 Hz), 8.19 (1 H, d, J = 5.83 Hz), 8.91 (1 H, s) 326T5-49.19

4-[1-(2- aminopyrimidin- 4-yl)-3- methyl-1H- indazol-6-yl]- 2-[5-(fluoromethyl) isoxazol-3-yl] but-3-yn-2- olmono- formate salt (500 MHz,MeOD) delta 1.96 (3 H, s), 2.59 (3 H, s), 5.49 (1 H, d, J = 47.3 Hz),6.79 (1 H, d, J = 3.5 Hz), 7.21 (1 H, d, J = 5.8 Hz), 7.40 (1 H, dd, J =8.20, 1.1 Hz), 7.74 (1 H, d, J = 8.2 Hz), 8.13 (1 H, s), 8.19 (1 H, d, J= 5.8 Hz), 8.98 (1 H, s); 393.0 T5-49.20

4-[1-(2- aminopyrimidin- 4-yl)-3- methyl-1H- indazol-6-yl]- 2-hydroxy-N,N,2- trimethylbut-3- ynamide: (500 MHz, DMSO) delta 1.66 (3 H, s),2.53 (3 H, s), 2.87 (3 H, s), 3.33 (3 H, s), 7.04 (1 H, d, J = 5.67 Hz),7.34 (1 H, dd, J = 8.20, 0.95 Hz), 7.81 (1 H, d, J = 8.20 Hz), 8.22 (1H, d, J = 5.36 Hz), 8.82 (1 H, s); 365.10 T5-49.21

3-{[1-(2- aminopyrimidin- 4-yl)-3- methyl-1H- indazol-6-yl] ethynyl}-3-hydroxy- 1- methylpyrrolidin- 2-one (500 MHz, 9:1 Methanol-d4:CDCl₃)delta 2.32-2.38 (1 H, m), 2.59 (3 H, s), 2.64 (1 H, ddd, J = 12.93,6.78, 4.57 Hz), 2.95 (3 H, s), 3.47- 3.53 (2 H, m), 4.53 (1 H, s), 7.19(1 H, d, J = 5.67 Hz), 7.37 (1 H, dd, J = 8.51, 1.26 Hz), 7.70 (1 H, dd,J = 8.20, 0.95 Hz), 8.18 (1 H, d, J = 5.36 Hz), 9.01 (1 H, s); 363.1

Example 50 Preparation of4-[1-(2-aminopyrimidin-4-yl)-1H-indazol-6-yl]-2-(1H-pyrazol-4-yl)but-3-yn-2-ol

The title compound was prepared by the procedure described in Example 2(Step 2-b) by reacting 4-(6-bromo-1H-indazol-1-yl)pyrimidin-2-amine with2-(1H-pyrazol-4-yl)but-3-yn-2-ol. The reaction was carried out at 75° C.for 1 hr: ¹H NMR (500 MHz, DMSO) delta 1.81 (3H, s), 5.95 (1H, br. s.),6.93-7.17 (3H, m), 7.38 (1H, d, J=9.30 Hz), 7.70 (2H, br. s.), 7.88 (1H,d, J=8.35 Hz), 8.31 (1H, d, J=5.52 Hz), 8.49 (1H, s), 8.91 (1H, s),12.71 (1H, br. s.); LC-MS: m/z=+346.50 (M+H)+.

Example 51 Preparation of4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-(1,3-oxazol-4-yl)but-3-yn-2-ol

Step 1—Synthesis of 4-(6-iodo-3-methylindazol-1-yl)pyrimidin-2-amine

A pressure tube containing copper (I) iodide (37.57 mg, 0.20 mmol),sodium iodide (591.42 mg, 3.95 mmol) and4-(6-bromo-3-methyl-1H-indazol-1-yl)pyrimidin-2-amine (600 mg, 1.97mmol) was flushed with nitrogen before the addition of 1,4-dioxane, DMF(3 ml each) and N,N′-dimethylethane-1,2-diamine (0.021 ml, 0.20 mmol).The vessel was sealed and stirred at 115° C. overnight. Reaction wascooled and added to ice water (15 ml) before extracting into DCM (2×20mL). Combined organics were dried (Na₂SO₄), filtered and concentrated invacuo. Crude material purified by column chromatography (Elution with 2%MeOH-DCM to 12% MeOH-DCM) to give the title compound: ¹H NMR (500 MHz,DMSO) delta 7.02 (3H, dd, J=5.5, 3.1 Hz), 7.73-7.53 (2H, m), 8.25 (1H,d, J=5.5 Hz), 9.25 (1H, s); LC-MS: m/z=+351.90 (M+H)+. This compound of79% purity LC-MS was used for the next step without further purification

Step 2—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-(1,3-oxazol-4-yl)but-3-yn-2-ol

To a vial was added 4-(6-iodo-3-methylindazol-1-yl)pyrimidin-2-amine(150 mg, 0.43 mmol), piperidine (1.5 mL),tetrakis(triphenylphosphine)palladium (49.36 mg, 0.04 mmol), copper(I)iodide (8.14 mg, 0.04 mmol) and 2-(1,3-oxazol-4-yl)but-3-yn-2-ol (87.87mg, 0.64 mmol). The mixture was stirred at RT for 20 mins Reactionmixture was concentrated in vacuo. DCM (5 mL) added and mixture wasconcentrated in vacuo. This was repeated twice. The crude material waspurified by column chromatography (Biotage, 98:2 to 88:12 DCM: methanolgradient). Further purification by flash column chromatography gave thetitle compound: ¹H (500 MHz, DMSO) delta 1.81 (3H, s), 2.58 (3H, s),6.26 (1H, s), 6.99 (2H, s), 7.04 (1H, d, J=5.5 Hz), 7.39 (1H, dd, J=8.2,1.1 Hz), 7.85 (1H, d, J=8.1 Hz), 8.13 (1H, s), 8.26 (1H, d, J=5.5 Hz),8.36 (1H, s), 8.87 (1H, s); LC-MS: m/z=+361.05 (M+H)+.

Example 52

Examples in Table 6 were prepared by procedure as described in Example51 (Step 2) by reacting 4-(6-iodo-3-methylindazol-1-yl)pyrimidin-2-aminewith the appropriate but-3-yn-2-ol.

TABLE 6 MS No. Structure Name 1H NMR (M + H) T6-52.1

4-[1-(2- aminopyrimidin- 4-yl)-3-methyl-1H- indazol-6-yl]-2-(5-methylpyrazin- 2-yl)but- 3-yn-2-ol; formic acid (500 MHz, DMSO) delta1.88 (3 H, s), 2.52 (3 H, s), 2.57 (2 H, s), 6.62 (1 H, br. s.), 6.99 (2H, br. s.), 7.03 (1 H, d, J = 5.67 Hz), 7.34 (1 H, dd, J = 8.28, 1.18Hz), 7.83 (1 H, d, J = 8.20 Hz), 8.14 (1 H, s), 8.25 (1 H, d, J = 5.52Hz), 8.53 (1 H, s), 8.85 (1 H, s), 8.90 (1 H, d, J = 1.26 Hz) 385.95T6-52.2

3-{2-[1-(2- aminopyrimidin- 4-yl)-3-methyl- 1H-indazol-6-yl]ethynyl}-3-hydroxy-1- methylpiperidin-2-one; formic acid (500 MHz, DMSO)delta 1.89-2.13 (3 H, m), 2.26 (1 H, td, J = 5.99, 3.78 Hz), 2.33-2.39(1 H, m), 2.58 (3 H, s), 2.64 (1 H, d, J = 1.73 Hz), 2.88 (3 H, s), 6.16(1 H, br. s.), 6.99 (2 H, br. s.), 7.04 (1 H, d, J = 5.52 Hz), 7.34 (1H, dd, J = 8.20, 1.10 Hz), 7.85 (1 H, d, J = 8.20 Hz), 8.27 (1 H, d, J =5.52 Hz), 8.35 (1 H, br. s.), 8.85 (1 H, s) 377.15

Example 53 Preparation of4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-(1-methyl-1H-imidazol-2-yl)but-3-yn-2-ol

Step 1—Synthesis of4-{3-methyl-6-[2-(trimethylsilyl)ethynyl]indazol-1-yl}pyrimidin-2-amine

To a pressure tube was added4-(6-bromo-3-methylindazol-1-yl)pyrimidin-2-amine (0.5 g, 1.64 mmol),piperidine (3.5 mL) tetrakis(triphenylphosphine)palladium (113.98 mg,0.1 mmol), copper(I) iodide (18.79 mg, 0.1 mmol) andethynyl(trimethyl)silane (0.47 ml, 3.29 mmol). The mixture was purgedwith nitrogen for 2 minutes and then stirred at 65° C. for 1.5 hr. Thereaction mixture was concentrated in vacuo, DCM (5 mL) was added and theconcentration repeated (×2). The mixture was purified by columnchromatography (Biotage, 3-8% MeOH gradient in DCM) to give the titleintermediate as a white solid (116 mg): ¹H NMR (250 MHz, DMSO) delta0.28 (9H, s), 2.57 (3H, s), 7.03 (3H, d, J=5.5), 7.38 (1H, d, J=8.2),7.84 (1H, d, J=8.2), 8.26 (1H, d, J=5.5), 8.90 (1H, s); LC-MS:m/z=+322.50 (M+H)+.

Step 2—Synthesis of 4-(6-ethynyl-3-methylindazol-1-yl)pyrimidin-2-amine

To a solution of4-{3-methyl-6-[2-(trimethylsilyl)ethynyl]indazol-1-yl}pyrimidin-2-amine(600 mg, 1.87 mmol) in THF (15 ml) was added TBAF (2.24 mL of a 1Msolution in THF, 2.24 mmol) and the reaction mixture was allowed tostand for 0.5 hr. The reaction mixture was concentrated in vacuo, DCM (5ml) was added and the concentration repeated (×2). The crude product waspurified by flash chromatography (Biotage, 3-10% methanol in DCM) togive the title intermediate as a yellow solid (300 mg): ¹H NMR (500 MHz,DMSO) delta 2.58 (3H, s), 4.37 (1H, s), 7.14-6.86 (3H, m), 7.40 (1H, dd,J=8.2, 1.1 Hz), 7.85 (1H, d, J=8.2 Hz), 8.26 (1H, d, J=5.5 Hz), 8.98(1H, s); LC-MS: m/z=+250.35 (M+H)+.

Step 3—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-(1-methyl-1H-imidazol-2-yl)but-3-yn-2-ol

To a solution of 4-(6-ethynyl-3-methylindazol-1-yl)pyrimidin-2-amine(150 mg, 0.6 mmol) in THF (2 mL) at −78° C. under nitrogen was added 2MLDA in THF (0.75 mL, 1.50 mmol). After 5 minutes,1-(1-methyl-1H-imidazol-2-yl)ethanone (225 mg, 1.81 mmol) in THF (1.0mL) was added, and after a further 20 minutes the mixture was allowed towarm to RT and stirred for 1.5 hours. The reaction mixture was thencooled to −78° C. and treated with additional 2M LDA in THF (0.3 mL, 0.6mmol) and 1-(1-methyl-1H-imidazol-2-yl)ethanone (90 mg, 0.6 mmol). Afterstirring at RT for 4 hr, the reaction mixture was quenched by additionof saturated aqueous NH₄Cl (2 mL). The volatiles were removed in vacuoand the mixture was diluted with DCM (10 ml) and washed with water (2mL), dried (Na₂SO₄), filtered and concentrated in vacuo. The crudeproduct was purified by flash chromatography (Biotage, 3-12% methanolgradient in DCM) to give the title compound: ¹H NMR (500 MHz, DMSO)delta 2.00 (3H, s), 2.57 (3H, s), 3.92 (3H, s), 6.32 (1H, s), 6.77 (1H,s), 6.98 (2H, s), 7.03 (1H, d, J=5.5 Hz), 7.15 (1H, s), 7.36 (1H, d,J=8.2), 7.84 (1H, d, J=8.2 Hz), 8.25 (1H, d, J=5.5 Hz), 8.84 (1H, s);LC-MS: m/z=+374.05 (M+H)+.

Example 54 Preparation of4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-(1H-1,2,4-triazol-3-yl)but-3-yn-2-ol

Step 1—Synthesis of 1-(oxan-2-yl)-1,2,4-triazole-3-carbonitrile

To a solution of 1H-1,2,4-triazole-3-carbonitrile (1.00 g, 10.63 mmol)in DCE (10 mL) was added 3,4-dihydro-2H-pyran (1.94 ml, 21.26 mmol) andp-toluenesulfonic acid (183 mg, 1.06 mmol). The resulting mixture wasstirred at room temperature under nitrogen for 15 minutes. Saturatedaqueous sodium bicarbonate solution (25 mL) was added and the productextracted into DCM (25 mL×3). The combined organics were washed withbrine (10 mL), dried (Na₂SO₄) and concentrated in vacuo. The crudeproduct was purified by flash chromatography (Biotage, 0-10% methanolgradient in DCM) to give the title intermediate as a yellow oil: ¹H NMR(500 MHz, CDCl₃) delta 1.81-1.63 (3H, m), 2.11-1.95 (2H, m), 2.19 (1H,dd, J=8.1, 5.6 Hz), 3.87-3.65 (1H, m), 4.18-3.97 (1H, m), 5.53 (1H, dd,J=8.5, 2.9 Hz), 8.37 (1H, s).

Step 2—Synthesis of 1-[1-(oxan-2-yl)-1,2,4-triazol-3-yl]ethanone

To a solution of methylmagnesium bromide (13.75 mL of a 3.2M solution in2-methyltetrahydrofuran, 6.29 mmol) was added slowly1-(oxan-2-yl)-1,2,4-triazole-3-carbonitrile (1.12 g, 6.29 mmol) inanhydrous THF (20 mL). The reaction mixture was stirred at 40° C. for 3h, cooled to ambient temperature and methanol (10 mL) added dropwise.The reaction mixture was stirred for 3 h and the precipitate removed byvacuum filtration. The filtrate was collected, silica gel (10 g) wasadded and the mixture stirred at RT for 15 hr. Water (10 ml) wasintroduced and the volatiles were removed in vacuo. The product wasextracted into EtOAc (25 mL×2) and the combined organics were washedwith water (10 mL) and dried (Na₂SO₄), filtered and concentrated invacuo. The aqueous phase was re-extracted with chloroform:isopropanol(3:1, 2×25 mL extractions) and the washes repeated before combining withthe EtOAc extracts and concentrating in vacuo. The crude product waspurified by flash chromatography (Biotage, 0-8% methanol gradient inDCM) to give of the title intermediate as a yellow oil: ¹H NMR (250 MHz,CDCl₃) delta 1.70 (3H, dd, J=4.7, 2.9 Hz), 2.39-1.94 (3H, m), 2.67 (3H,s), 3.91-3.63 (1H, m), 4.27-4.01 (1H, m), 5.71-5.42 (1H, m), 8.35 (1H,s); LC-MS: m/z=+391.10 (2M+1)+. This compound of 78% purity LC-MS (UV)was used without further purification.

Step 3—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-3-methylindazol-6-yl]-2-[1-(oxan-2-yl)-1,2,4-triazol-3-yl]but-3-yn-2-ol

To a solution of 4-(6-ethynyl-3-methylindazol-1-yl)pyrimidin-2-amine (90mg, 0.36 mmol) in dry THF (1.5 mL) at −78° C. under an atmosphere ofnitrogen was added 2M LDA in THF (0.45 mL, 0.903 mmol). After 5 minutes,1-[1-(oxan-2-yl)-1,2,4-triazol-3-yl]ethanone (211.45 mg in 1.5 mL dryTHF, 1.08 mmol) was added. After 20 minutes the mixture was allowed towarm up to RT, then stirred for a further 30 minutes. The reactionmixture was quenched by addition of saturated aqueous NH₄Cl (0.5 mL).The volatiles were removed in vacuo and the mixture was diluted with DCM(10 ml) and washed with water (2 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product was purified by flashchromatography (Biotage, 2-11% methanol gradient in DCM) to give thetitle intermediate as a pale yellow oil: ¹H NMR (500 MHz, DMSO) delta1.76-1.56 (3H, m), 1.90 (3H, s), 2.18-1.94 (3H, m), 2.58 (3H, s),3.74-3.60 (1H, m), 4.03-3.87 (1H, m), 5.60-5.43 (1H, m), 6.27 (1H, s),6.96 (2H, s), 7.04 (1H, d, J=5.5 Hz), 7.34 (1H, d, J=8.1 Hz), 7.84 (1H,d, J=8.4 Hz), 8.26 (1H, d, J=5.5 Hz), 8.68 (1H, s), 8.84 (1H, s); LC-MS:m/z=+445.05 (M+H)+.

Step 4—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-(1H-1,2,4-triazol-3-yl)but-3-yn-2-ol

To a solution of4-[1-(2-aminopyrimidin-4-yl)-3-methylindazol-6-yl]-2-[1-(oxan-2-yl)-1,2,4-triazol-3-yl]but-3-yn-2-ol(60 mg, 0.13 mmol) in methanol (3 mL) was added p-toluenesulfonic acid(25.38 mg, 0.15 mmol). The reaction mixture was stirred at 55° C. for 1hr, and then concentrated in vacuo. The crude residue was partitionedbetween saturated NaHCO₃ solution (2 ml) and DCM (2×5 ml). The combinedorganic extracts were washed with brine (2 mL), dried (Na₂SO₄), filteredand concentrated in vacuo. The crude product was purified by flashchromatography (Isolute column, 2-10% methanol gradient in DCM) to givethe title compound: ¹H NMR (500 MHz, DMSO) delta 1.92 (3H, s), 2.58 (3H,s), 6.96 (2H, s), 7.05 (1H, d, J=5.5 Hz), 7.46-7.28 (1H, m), 7.85 (1H,d, J=8.2 Hz), 8.26 (1H, d, J=5.5 Hz), 8.86 (1H, s), 14.01 (1H, s);LC-MS: m/z=+361.05 (M+H)+.

Example 55 Preparation of4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-(1H-imidazol-4-yl)but-3-yn-2-ol

Step 1—Synthesis of 1-[1-(triphenylmethyl)imidazol-4-yl]ethanone

To a solution of 1-(1H-imidazol-4-yl)ethanone (200 mg, 1.82 mmol) in DMF(4 mL) was introduced triethylamine (0.38 mL, 2.72 mmol) and tritylchloride (506.34 mg, 1.82 mmol). The reaction mixture was stirred atroom temperature for 2 h. Aqueous brine solution (5 mL) was added to thereaction mixture and the product extracted with EtOAc (2×10 mL). Thecombined organics were dried (Na₂SO₄), filtered and concentrated invacuo. The crude product was purified by flash chromatography (Isolute,1-10% methanol gradient in DCM) to give the title intermediate as aclear oil: ¹H NMR (500 MHz, CDCl₃) delta 2.55 (3H, s), 7.18-7.06 (6H,m), 7.40-7.29 (9H, m), 7.44 (1H, d, J=1.3 Hz), 7.58 (1H, d, J=1.4 Hz);LC-MS: m/z=+375.10 (M+Na)+.

Step 2—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-3-methylindazol-6-yl]-2-[1-(triphenylmethyl)imidazol-4-yl]but-3-yn-2-ol

To a solution of 4-(6-ethynyl-3-methylindazol-1-yl)pyrimidin-2-amine(180 mg at 90% purity, 0.65 mmol) in THF (2.5 mL) at −78° C. undernitrogen was added 2M LDA in THF (0.81 mL, 1.63 mmol). After 5 minutes1-[1-(triphenylmethyl)imidazol-4-yl]ethanone (458.08 mg, 1.3 mmol) inTHF (1.5 mL) was added. After 20 minutes, the mixture was allowed towarm up to RT and stirred for a further 1 hr. The reaction mixture wasquenched by addition of saturated aqueous NH₄Cl (1 mL). The volatileswere removed in vacuo and the mixture was diluted with DCM (10 ml) andwashed with water (2 mL), dried (Na₂SO₄), filtered and concentrated invacuo. The crude product was purified by flash chromatography (Biotage,2-12% methanol gradient in DCM) to give the title intermediate as ayellow oil: ¹H NMR (500 MHz, CDCl₃) delta 1.96 (3H, s), 2.58 (3H, s),4.41 (1H, s), 5.36 (2H, s), 6.96 (1H, d, J=1.0), 7.19-7.09 (6H, m), 7.24(1H, d, J=5.7 Hz), 7.35-7.30 (10H, m), 7.44 (1H, d, J=1.0 Hz), 7.53 (1H,d, J=8.2), 8.24 (1H, d, J=5.7), 8.83 (1H, s); LC-MS: m/z=+360.35(M-C(C₆H₅)₃)+.

Step 3—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-(1H-imidazol-4-yl)but-3-yn-2-ol

To a solution of4-[1-(2-aminopyrimidin-4-yl)-3-methylindazol-6-yl]-2-[1-(triphenylmethyl)imidazol-4-yl]but-3-yn-2-ol(45 mg, 0.07 mmol) in DCM (2 ml) was added trifluoroacetic acid (0.4ml). The reaction was allowed to stand at RT for 0.5 hr and thenconcentrated in vacuo. DCM (5 mL) and saturated aqueous sodiumbicarbonate (2 mL) were added and the organics extracted (4×5 mL DCMextractions). The combined extracts were dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product was purified by flashchromatography (Isolute, 0-10% methanol gradient in DCM) to surrenderthe title compound as a pale brown solid: ¹H NMR (250 MHz, MeOD) delta1.92 (3H, s), 2.58 (3H, s), 7.28-7.14 (2H, m), 7.39 (1H, dd, J=8.2, 1.2Hz), 7.82-7.64 (2H, m), 8.19 (1H, d, J=5.8 Hz), 8.98 (1H, s); LC-MS:m/z=+360.05 (M+H)+.

Example 56 Preparation of4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)but-3-yn-2-ol

Step 1—Synthesis of1-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)ethanone

To a solution of 1-(1H-imidazol-2-yl)ethanone (550 mg, 4.99 mmol), 3.18mmol) in DCM (20 mL) was added DIPEA (1.74 ml, 9.99 mmol) and SEMchloride (0.87 ml dissolved in 5 mL DCM, 4.99 mmol). The resultingmixture was stirred at RT for 1 hr. Saturated aqueous sodium bicarbonate(10 mL) was then added and the aqueous phase was extracted with DCM(3×10 mL extractions). The combined organic extracts were dried(Na₂SO₄), filtered and concentrated in vacuo to give the titleintermediate as a yellow oil: ¹H NMR (500 MHz, CDCl₃) delta 0.00 (9H,s), 1.03-0.82 (2H, m), 2.66 (3H, s), 3.66-3.38 (2H, m), 5.76 (2H, s),7.18 (1H, s), 7.28 (1H, s); LC-MS: m/z=+241.00 (M+H)+.

Step 2—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)but-3-yn-2-ol

To a solution of1-(2-aminopyrimidin-4-yl)-6-ethynyl-N,N-dimethylindazole-3-carboxamide(200 mg, 0.8 mmol) in THF (2 mL) at −78° C. under nitrogen was added 2MLDA in THF (1.40 mL, 2.81 mmol). After 1 hour,1-(1-{[2-(trimethylsilyl)ethoxy]methyl}imidazol-2-yl)ethanone (771.45mg, 3.21 mmol) in THF (1.0 mL) was added. After stirring for 15 minutes,the reaction mixture was allowed to warm to RT and stirred for 2 hr. Thereaction mixture was quenched by addition of saturated aqueous ammoniumchloride (3 mL) and the volatiles were removed in vacuo. The reactionmixture was diluted with DCM (10 ml) and washed with water (2 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. The crude product waspurified by flash chromatography (Biotage, 1-12% methanol gradient inDCM) to surrender the title compound as a yellow solid: ¹H NMR (500 MHz,DMSO) delta −0.19 (9H, s), 0.83-0.77 (2H, m), 2.01 (3H, s), 2.57 (3H,s), 3.59-3.49 (2H, m), 5.62 (1H, d, J=10.3 Hz), 5.78 (1H, d, J=10.2 Hz),6.42 (1H, s), 6.86 (1H, d, J=1.1 Hz), 6.96 (2H, s), 7.03 (1H, d, J=5.5Hz), 7.27 (1H, d, J=1.0 Hz), 7.36 (1H, dd, J=8.1, 1.1 Hz), 7.84 (1H, d,J=8.2 Hz), 8.25 (1H, d, J=5.5 Hz), 8.85 (1H, s); LC-MS: m/z=+490.10(M+H)+

Example 57 Preparation of4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-(1H-imidazol-2-yl)but-3-yn-2-ol

A solution of4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)but-3-yn-2-olin 4M HCl in dioxane (2.5 ml) was stirred at 40° C. for 2 h and then at50° C. for a further 1 hr. The reaction mixture was then concentrated invacuo and basified using saturated aqueous sodium bicarbonate solution.The product was extracted into DCM (2×3 mL) and the combined organicswere washed with brine solution (2 ml), dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude product was purified by flashchromatography (Biotage, 5-12% methanol gradient in DCM) to give thetitle compound as an off-white solid: ¹H NMR (500 MHz, DMSO) delta 1.90(3H, s), 2.57 (3H, s), 6.42 (1H, s), 6.83 (1H, s), 6.96 (2H, s),7.10-6.99 (2H, m), 7.35 (1H, d, J=8.2 Hz), 7.84 (1H, d, J=8.2 Hz), 8.25(1H, d, J=5.5 Hz), 8.86 (1H, s), 12.01 (1H, s); LC-MS: m/z=+360.05(M+H)+.

Example 58 Preparation of4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-hydroxy-1-(3-hydroxyazetidin-1-yl)-2-methylbut-3-yn-1-one

Step 1 Synthesis of ethyl4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-hydroxy-2-methylbut-3-ynoate

To a solution of 4-(6-iodo-3-methyl-1H-indazol-1-yl)pyrimidin-2-amine(170 mg, 0.38 mmol) in dry THF (3 mL) was introducedbis(triphenylphosphine)palladium(II) chloride (27 mg, 0.04 mmol), ethyl2-hydroxy-2-methyl-4-(trimethylsilyl)but-3-ynoate (164 mg, 0.76 mmol)and TBAF (0.46 mL of a 1M solution in THF, 0.46 mmol). The solution waswarmed to 50° C. for 1.5 hr. After cooling, sodium bicarbonate (4 mL ofsaturated aqueous NaHCO₃) was introduced and the solution extracted withEtOAc (3×10 mL extractions). The combined organic extracts were washedwith brine (10 mL), dried (Na₂SO₄), filtered and concentrated in vacuo.Purification by silica gel flash column chromatography (DCM containing a1-10% gradient of methanol) furnished the title compound as an orangeoil: ¹H NMR (250 MHz, Chloroform-d) delta 1.39 (3H, t, J=7.1 Hz), 1.83(3H, s), 2.60 (3H, s), 4.38 (2H, q, J=7.1 Hz), 5.20 (2H, s), 7.29 (1H,s), 7.34 (1H, dd, J=8.2, 1.3 Hz), 7.60 (1H, dd, J=8.2, 0.7 Hz), 8.29(1H, d, J=5.7 Hz), 8.83 (1H, s); LC-MS: m/z=+366.05 (M+H)+.

Step 2—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-hydroxy-2-methylbut-3-ynoicAcid

To a solution of ethyl4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-hydroxy-2-methylbut-3-ynoate(120 mg, 0.33 mmol) in methanol (0.5 mL) was introduced sodium hydroxide(0.16 mL of a 2M aqueous solution, 0.33 mmol). After 15 hr at RT, thereaction mixture was concentrated in vacuo and the pH of the aqueousresidue adjusted to 7 with 0.5M aqueous hydrochloric acid. The solutionwas extracted with 3:1 chloroform/isopropanol (5×5 mL extractions) andthe combined organic extracts dried (Na₂SO₄), filtered and concentratedin vacuo to furnish the crude title compound as a yellow solid: ¹H NMR(250 MHz, DMSO) delta 1.68 (3H, s), 2.59 (3H, s), 7.07-7.29 (3H, m),7.37 (2H, dd, J=8.4, 1.2 Hz), 7.87 (1H, d, J=7.7 Hz), 8.28 (1H, d, J=5.9Hz), 8.85 (1H, s); LC-MS: m/z=+338.00 (M+H)+. This compound, with LC-MSpurity=100% UV, was used in the next step without further purification.

Step 3—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-hydroxy-1-(3-hydroxyazetidin-1-yl)-2-methylbut-3-yn-1-one

To a solution of4-[1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-hydroxy-2-methylbut-3-ynoicacid (100 mg, 0.30 mmol) in DMF (3 mL) was introducedO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (225 mg, 0.59 mmol), azetidin-3-ol hydrochloride (65mg, 0.59 mmol) and triethylamine (0.12 mL, 0.89 mmol). After 18 hr atRT, the solution was re-treated withO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (225 mg, 0.59 mmol), azetidin-3-ol hydrochloride (65mg, 0.59 mmol) and triethylamine (0.12 mL, 0.89 mmol). After 3 hr at RT,the reaction mixture was diluted with water (2 mL) and extracted withEtOAc (2×5 mL extractions). The combined organic extracts were washedwith water (5 mL) and brine (5 ml), dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the residue by silica gel flashcolumn chromatography (DCM containing a 2-10% gradient of methanol)furnished the title compound as a colorless solid: ¹H NMR (500 MHz,DMSO) delta 1.64 (3H, s), 2.58 (3H, s), 3.58-3.75 (1H, m), 4.09-4.19(1H, m), 4.19-4.28 (1H, m), 4.49 (1H, s), 4.63-4.76 (1H, m), 5.67-5.81(1H, m), 6.14 (1H, d, J=17.5 Hz), 6.98 (2H, s), 7.05 (1H, d, J=5.5 Hz),7.38 (1H, d, J=8.7 Hz), 7.87 (1H, dd, J=8.2, 1.8 Hz), 8.27 (1H, d, J=5.5Hz), 8.87 (1H, s); LC-MS: m/z=+393.05 (M+H)+.

Example 59 Preparation of(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-[(3,3-difluoroazetidin-1-yl)methyl]-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

Step 1—Synthesis of6-bromo-3-[(3,3-difluoroazetidin-1-yl)methyl]-1H-indazole

The title compound was prepared by the procedure described in Example12-a by substituting 2M dimethylamine in THF with 3,3-difluoroazetidinein Step 1: ¹H NMR (500 MHz, CDCl₃) delta 2.55 (4H, br. s.), 3.73 (4H, t,J=4.57 Hz), 3.91 (2H, s), 7.22-7.30 (1H, m), 7.63 (1H, s), 7.72 (1H, s),7.78 (1H, d, J=8.67 Hz); LC-MS: m/z=+295.90/297.85 (M+H)+.

Step 2-Synthesis of4-{6-bromo-3-[(3,3-difluoroazetidin-1-yl)methyl]indazol-1-yl}pyrimidin-2-amine

The title compound was prepared by the procedure described in Example12-b by substituting 1-(6-bromo-1H-indazol-3-yl)-N,N-dimethylmethanaminewith 6-bromo-3-[(3,3-difluoroazetidin-1-yl)methyl]-1H-indazole in Step2: ¹H NMR (250 MHz, CDCl₃) delta 2.89 (1H, s), 2.96 (1H, s), 3.73 (4H,t, J=12.03 Hz), 4.13 (2H, s), 7.15-7.33 (1H, m), 7.43 (1H, dd, J=8.45,1.60 Hz), 7.76 (1H, d, J=8.53 Hz), 8.32 (1H, d, J=5.63 Hz), 8.98 (1H, d,J=1.22 Hz); LC-MS: m/z=+395.00/396.80 (M+H)+.

Step 3—Synthesis of(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-[(3,3-difluoroazetidin-1-yl)methyl]-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

The title compound was prepared by the procedure described in Example10-c by substituting4-{6-bromo-3-[(dimethylamino)methyl]-1H-indazol-1-yl}pyrimidin-2-aminewith of4-{6-bromo-3-[(3,3-difluoroazetidin-1-yl)methyl]indazol-1-yl}pyrimidin-2-amineand 2-methyl-but-3-yn-2-ol with(2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol: ¹H NMR (500 MHz,CDCl₃) delta 2.09 (3H, s), 2.67 (3H, s), 3.73 (4H, t, J=12.06 Hz), 4.12(2H, s), 4.80-5.13 (1H, m), 5.51 (2H, s), 7.28 (1H, d, J=5.67 Hz), 7.37(1H, dd, J=8.28, 1.02 Hz), 7.79 (1H, d, J=8.20 Hz), 8.30 (1H, d, J=5.67Hz), 8.86 (1H, s); LC-MS: m/z=+467.1 (M+H)+.

Example 60

Examples in Table 7 were prepared by procedure described in Example 6 byreacting the 4-[6-bromo-1H-indazol-1-yl]pyrimidin-2-amine derivativeswith the appropriate but-3-yn-2-ol.

TABLE 7 MS No. Structure Name 1H NMR (M + H) T7-60.1

4-[1-(2- aminopyrimidin- 4-yl)-3- [(dimethylamino) methyl]-1H-indazol-6-yl]-2-(1,3- oxazol-2-yl)but-3-yn- 2-ol (500 MHz, DMSO) delta 1.95 (3H, s), 2.24 (6 H, s), 3.82 (2 H, s), 6.96-7.09 (3 H, m), 7.24 (1 H, s),7.37 (1 H, d, J = 8.20 Hz), 7.98 (1 H, d, J = 8.35 Hz), 8.15 (1 H, s),8.28 (1 H, d, J = 5.52 Hz), 8.90 (1 H, s) 404.1 T7-60.2

(2R)-4-[1-(2- aminopyrimidin- 4-yl)- 3-(morpholin-4- ylmethyl)-1H-indazol-6-yl]-2-(5- methyl-1,2-oxazol- 3-yl)but-3-yn-2-ol (500 MHz,DMSO) delta 1.86 (3 H, s), 2.42 (3 H, s), 2.47 (4 H, br. s.), 3.57 (4 H,t, J = 4.18 Hz), 3.90 (2 H, s), 6.41 (1 H, s), 6.57 (1 H, s), 7.03 (2 H,br. s.), 7.06 (1 H, d, J = 5.52 Hz), 7.37 (1 H, dd, J = 8.35, 1.10 Hz),8.03 (1 H, d, J = 8.20 Hz), 8.28 (1 H, d, J = 5.52 Hz), 8.88 (1 H, s)460.1 T7-60.3

4-[1-(2- aminopyrimidin- 4-yl)-3- (morpholin-4- ylmethyl)-1H-indazol-6-yl]-2-(pyrimidin- 2-yl)but-3-yn-2- ol (500 MHz, CDCl₃) delta 2.17 (3H, s), 2.45- 2.63 (4 H, m), 3.71 (4 H, t, J = 4.49 Hz), 3.88 (2 H, s),5.35 (2 H, br. s.), 5.52 (1 H, br. s.), 7.26 (1 H, br. s.), 7.30- 7.39(2 H, m), 7.85 (1 H, d, J = 8.20 Hz), 8.28 (1 H, br. s.), 8.84 (3 H, br.s.) 457.1 T7-60.4

4-[1-(2- aminopyrimidin- 4-yl)-3-[(3,3- difluoroazetidin-1-yl)methyl]-1H- indazol-6-yl]-2- (pyrimidin-2-yl) but-3-yn-2-ol (500MHz, CDCl₃) delta 2.06 (3 H, s), 3.73 (4 H, t, J = 12.14 Hz), 4.12 (2 H,s), 5.21 (2 H, s), 5.38 (1 H, s), 7.29 (1 H, d, J = 5.52 Hz), 7.32-7.40(2 H, m), 7.76 (1 H, d, J = 8.35 Hz), 8.31 (1 H, br. s.), 8.86 (3 H, d,J = 2.84 Hz) 463.05

Example 61 Preparation of1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(1,3-thiazol-2-yl)but-1-yn-1-yl]-N,N-dimethyl-1H-indazole-3-carboxamide

Step 1—Synthesis of 6-bromo-N,N-dimethyl-1H-indazole-3-carboxamide

To a mixture of 6-bromo-1H-indazole-3-carboxylic acid (1 g, 4.15 mmol)and EDC.HCl (1.2 g, 6.2 mmol) in DMF (5 mL) was added 2 M dimethylaminein THF (3.45 mL, 10.3 mmol). Mixture was stirred at RT overnight. Thereaction mixture was concentrated in vacuo to remove the volatiles, thendiluted with EtOAc (30 mL) and washed with water. The aqueous layer wasextracted with more EtOAc (20 mL). The combined organics were washedwith water (30 mL), dried (Na₂SO₄), filtered and concentrated in vacuoto give the title compound as a white solid: ¹H NMR (250 MHz, DMSO)delta 3.06 (3H, s), 7.34 (1H, dd, J=8.68, 1.52 Hz), 7.84 (1H, d, J=1.07Hz), 7.92 (1H, d, J=8.68 Hz), 13.62 (1H, br. s.); LC-MS: m/z=+269.75(M+H)+.

Step 2: Synthesis of1-(2-aminopyrimidin-4-yl)-6-bromo-N,N-dimethylindazole-3-carboxamide

To a solution of 6-bromo-N,N-dimethyl-1H-indazole-3-carboxamide (95%,450 mg, 1.59 mmol) in DMF (10 mL) was added NaH (60% dispension inmineral oil) (60 mg, 1.02 mmol) at 0° C. Mixture was stirred at rt for10 mins before addition of 4-chloropyrimidin-2-amine (413 mg, 3.19mmol). The mixture was stirred at 65° C. overnight. The mixture wasquenched by addition of water (10 mL). The mixture was extracted withEtOAc (2×15 mL). The combined organics washed with water (10 mL), dried(Na₂SO₄), filtered and concentrated in vacuo. Trituration withDCM:heptane (4:1) gave the desired product. The filtrate wasre-filtered. The solids were combined to give the title compound; ¹H NMR(250 MHz, DMSO) delta 3.11 (3H, s), 3.32 (3H, s), 7.08 (1H, d, J=5.48Hz), 7.19 (1H, d, J=3.35 Hz), 7.58 (1H, dd, J=8.68, 1.68 Hz), 7.95 (1H,d, J=8.53 Hz), 8.34 (1H, d, J=5.63 Hz), 9.18 (1H, d, J=1.22 Hz); LC-MS:m/z=+362.8 (M+H)+.

Step 3: Synthesis of1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(1,3-thiazol-2-yl)but-1-yn-1-yl]-N,N-dimethyl-1H-indazole-3-carboxamide

To a sealed tube was added1-(2-aminopyrimidin-4-yl)-6-bromo-N,N-dimethylindazole-3-carboxamide(55%, 113 mg, 0.172 mmol), followed by piperidine (2 mL),tetrakis(triphenylphosphine)palladium (40 mg, 0.034 mmol), copper(I)iodide (7 mg, 0.034 mmol) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (105 mg,0.688 mmol). The reaction mixture was purged with nitrogen gas, cappedand stirred at 60° C. for 1.5 hr. Reaction mixture was concentrated invacuo. EtOAc (5 mL) added. Concentration in vacuo was repeated. Theresidue was purified using column chromatography (Biotage, 100% DCM to10% MeOH/DCM) to give a brown solid. Trituration of the solid with DCMgave the title compound: ¹H NMR (500 MHz, DMSO) delta 1.95 (3H, s), 3.12(3H, s), 3.33 (3H, s), 7.12 (2H, s), 7.13-7.19 (2H, m), 7.42 (1H, dd,J=8.35, 1.42 Hz), 7.71 (1H, d, J=3.31 Hz), 7.80 (1H, d, J=3.15 Hz),7.97-8.07 (1H, m), 8.35 (1H, d, J=5.52 Hz), 8.94 (1H, s); LC-MS:m/z=+434.45 (M+H)+.

Example 62 Preparation of4-[1-(2-aminopyrimidin-4-yl)-3-[(morpholin-4-yl)carbonyl]-1H-indazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

Step 1: Synthesis of 6-bromo-3-[(morpholin-4-yl)carbonyl]-1H-indazole

To a solution of 6-bromo-1H-indazole-3-carboxylic acid (500 mg, 2.07mmol) in DMF (10 mL) was added CDI (403.62 mg, 2.49 mmol) and thereaction mixture stirred at 45° C. for 40 minutes. Morpholine (0.36 ml,4.16 mmol) was then added and the reaction mixture stirred at RT. Thereaction mixture was quenched by diluting with water. The product wasextracted into EtOAc (×2) and the combined organic extracts were thenwashed with water and brine and dried (Na₂SO₄), filtered andconcentrated in vacuo to give the crude (78% pure) title compound: ¹HNMR (500 MHz, DMSO) delta 3.58-3.79 (6H, m), 3.96-4.13 (2H, m), 7.36(1H, dd, J=8.59, 1.66 Hz), 7.86 (1H, d, J=1.10 Hz), 7.93 (1H, s), 13.66(1H, br. s.); LC-MS: m/z=+311.70 (M+H)+.

Step 2: Synthesis of4-{6-bromo-3-[(morpholin-4-yl)carbonyl]indazol-1-yl}pyrimidin-2-amine

To a solution of 6-bromo-3-[(morpholin-4-yl)carbonyl]-1H-indazole (78%,458 mg, 1.15 mmol) in DMF (8 mL) was added NaH (60% oil suspension,73.71 mg, 1.84 mmol) at 0° C. Mixture was stirred at RT for 10 minutesbefore addition of 4-chloropyrimidin-2-amine (298.44 mg, 2.3 mmol). Themixture was stirred at RT for 10 minutes and then at 65° C. for 5 hr.Reaction mixture was quenched by addition of water (5 mL) and a littleEtOAc (2 mL) was added. Precipitate formed was collected and dried undervacuum to give the title compound: ¹H NMR (500 MHz, DMSO) delta3.58-3.80 (6H, m), 3.87-4.13 (2H, m), 7.07 (1H, d, J=5.52 Hz), 7.59 (1H,dd, J=8.51, 1.42 Hz), 7.94 (1H, d, J=8.83 Hz), 8.35 (1H, d, J=5.52 Hz),9.19 (1H, d, J=1.26 Hz); LC-MS: m/z=+404.8 (M+H)+.

Step 3: Synthesis of4-[1-(2-aminopyrimidin-4-yl)-3-[(morpholin-4-yl)carbonyl]-1H-indazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

The title compound was prepared by procedure described in Example 61-c,by substituting1-(2-aminopyrimidin-4-yl)-6-bromo-N,N-dimethylindazole-3-carboxamidewith4-{6-bromo-3-[(morpholin-4-yl)carbonyl]indazol-1-yl}pyrimidin-2-amineand 2-(1,3-thiazol-2-yl)but-3-yn-2-ol with2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol in Step 3: ¹H NMR (500 MHz,DMSO) delta 1.86 (3H, s), 2.42 (3H, s), 3.63-3.70 (2H, m), 3.70-3.80(4H, m), 3.89-3.97 (2H, m), 6.41 (1H, s), 6.58 (1H, s), 7.08 (1H, d,J=5.36 Hz), 7.16 (2H, br. s.), 7.44 (1H, dd, J=8.35, 1.26 Hz), 8.02 (1H,d, J=8.35 Hz), 8.35 (1H, d, J=5.36 Hz), 8.94 (1H, s); LC-MS: m/z=+474.4(M+H)+.

Example 63

Examples in Table 8 were prepared by procedure described in Example 61-cby reacting either1-(2-aminopyrimidin-4-yl)-6-bromo-N,N-dimethylindazole-3-carboxamide or4-{6-bromo-3-[(morpholin-4-yl)carbonyl]indazol-1-yl}pyrimidin-2-aminewith the appropriate but-3-yn-2-ol

TABLE 8 MS No. Structure Name 1H NMR (M + H) T8-63.1

1-(2- aminopyrimidin- 4-yl)-6-(3-hydroxy- 3-methylbut-1-yn-1-yl)-N,N-dimethyl- 1H-indazole-3- carboxamide (500 MHz, DMSO) delta1.53 (6 H, s), 3.11 (3 H, s), 3.32 (3 H, s), 5.54 (1 H, s), 7.11 (1 H,d, J = 4.26 Hz), 7.16 (2 H, br. s.), 7.39 (1 H, dd, J = 8.35, 1.26 Hz),7.98 (1 H, d, J = 8.35 Hz), 8.40 (1 H, br. s.), 8.90 (1 H, s) 365.45T8-63.2

1-(2- aminopyrimidin- 4-yl)-6-[3-hydroxy- 3-(1,3-oxazol-2-yl)but-1-yn-1-yl]-N,N- dimethyl-1H- indazole-3- carboxamide (250 MHz, DMSO)delta 1.95 (3 H, s), 3.12 (3 H, s), 3.31-3.33 (3 H, m), 6.82 (1 H, s),7.10 (1 H, d, J = 5.48 Hz), 7.17 (1 H, br. s.), 7.25 (1 H, d, J = 0.61Hz), 7.44 (1 H, dd, J = 8.38, 1.37 Hz), 7.96- 8.07 (1 H, m), 8.17 (1 H,d, J = 0.76 Hz), 8.35 (1 H, d, J = 5.33 Hz), 8.96 (1 H, s) 418.45T8-63.3

1-(2- aminopyrimidin- 4-yl)-6-[(3R)-3- hydroxy- 3-(1,3-thiazol-2-yl)but-1-yn-1- yl]-N,N-dimethyl- 1H-indazole-3- carboxamide (500 MHz,DMSO) delta 1.94 (3 H, s), 3.11 (3 H, s), 7.06-7.12 (2 H, m), 7.14 (2 H,br. s.), 7.41 (1 H, dd, J = 8.43, 1.18 Hz), 7.70 (1 H, d, J = 3.31 Hz),7.79 (1 H, d, J = 3.15 Hz), 8.00 (1 H, d, J = 8.35 Hz), 8.34 (1 H, d, J= 5.52 Hz), 8.93 (1 H, s) 434.4 T8-63.4

1-(2- aminopyrimidin- 4-yl)-6-[3-hydroxy- 3-(3-methyl- 1,2-oxazol-5-yl)but-1-yn- 1-yl]-N,N-dimethyl- 1H-indazole-3- carboxamide (500 MHz,DMSO) delta 1.86 (3 H, s), 2.25 (3 H, s), 3.11 (3 H, s), 6.45 (1 H, s),6.79 (1 H, s), 7.10 (2 H, d, J = 5.52 Hz), 7.15 (2 H, br. s.), 7.46 (1H, d, J = 8.35 Hz), 8.02 (1 H, d, J = 8.20 Hz), 8.35 (1 H, d, J = 5.36Hz), 8.97 (1 H, s) 432.45 T8-63.5

1-(2- aminopyrimidin- 4-yl)-6-[3-hydroxy- 3-(5-methyl-1,2- oxazol-3-yl)but-1-yn- 1-yl]-N,N-dimethyl- 1H-indazole-3- carboxamide (500 MHz,DMSO) delta 1.86 (3 H, s), 2.42 (3 H, s), 3.11 (3 H, s), 6.41 (1 H, s),6.58 (1 H, s), 7.10 (1 H, d, J = 5.52 Hz), 7.14 (2 H, br. s.), 7.43 (1H, dd, J = 8.35, 1.26 Hz), 8.01 (1 H, d, J = 8.35 Hz), 8.35 (1 H, d, J =5.52 Hz), 8.94 (1 H, s) 432.45 T8-63.6

1-(2- aminopyrimidin- 4-yl)-6-[3-hydroxy- 3-(5-methyl-1,2,4-oxadiazol-3-yl)but- 1-yn-1-yl]-N,N- dimethyl-1H- indazole-3- carboxamide(250 MHz, DMSO) delta 1.88 (3 H, s), 2.61 (3 H, s), 3.10 (3 H, s), 6.80(1 H, s), 7.08 (1 H, d, J = 5.79 Hz), 7.14 (2 H, br. s.), 7.42 (1 H, d,J = 8.53 Hz), 8.00 (1 H, d, J = 8.38 Hz), 8.33 (1 H, d, J = 5.63 Hz),8.94 (1 H, s) 433.1 T8-63.7

1-(2- aminopyrimidin- 4-yl)-6-[(3R)-3- hydroxy-3-(1,3- thiazol-2-yl)but-1-yn-1- yl]-N,N-dimethyl- 1H-indazole-3- carboxamide (250 MHz,DMSO) delta 1.95 (3 H, s), 3.11 (3 H, s), 3.32 (3 H, s), 7.09 (1 H, d, J5.5), 7.24- 7.12 (3 H, m), 7.42 (1 H, dd, J = 8.4, 1.3 Hz), 7.71 (1 H,d, J = 3.2 Hz), 7.79 (1 H, d, J = 3.2 Hz), 8.00 (1 H, dd, J = 8.4, 0.6Hz), 8.34 (1 H, d, J = 5.5 Hz), 8.93 (1 H, s). 434.05 T8-63.8

(2R)-4-[1- (2-aminopyrimidin- 4-yl)-3-[(morpholin- 4-yl)carbonyl]-1H-indazol- 6-yl]-2-(5-methyl- 1,2-oxazol-3-yl)but- 3-yn-2-ol (500 MHz,DMSO) delta 1.86 (3 H, s), 2.42 (3 H, s), 3.79-3.62 (6 H, m), 3.99-3.91(2 H, m), 6.42 (1 H, s), 6.60 (1 H, s), 7.08 (1 H, d, J = 5.5 Hz), 7.17(2 H, s), 7.44 (1 H, dd, J = 8.4, 1.2 Hz), 8.02 (1 H, d, J = 8.4 Hz),8.36 (1 H, d, J = 5.5 Hz), 8.95 (1 H, s). 474.5 T8-63.9

(2S)-4-[1-(2- aminopyrimidin- 4-yl)-3- [(morpholin-4-yl)carbonyl]-1H-indazol- 6-yl]-2-(5-methyl- 1,2-oxazol-3-yl)but- 3-yn-2-ol(500 MHz, DMSO) delta 1.86 (3 H, s), 2.42 (3 H, s), 3.81-3.60 (6 H, m),4.01-3.87 (2 H, m), 6.42 (1 H, s), 6.60 (1 H, s), 7.08 (1 H, d, J = 5.5Hz), 7.17 (2 H, s), 7.44 (1 H, dd, J = 8.4, 1.1 Hz), 8.03 (1 H, d, J =8.3 Hz), 8.36 (1 H, d, J = 5.5 Hz), 8.95 (1 H, s). 474.45 T8-63.10

1-(2- aminopyrimidin- 4-yl)-6-(2-{7-hydroxy- 5H,6H,7H-pyrrolo[1,2-c]imidazol- 7-yl}ethynyl)-N,N- dimethyl-1H-indazole- 3-carboxamide(500 MHz, DMSO) delta 2.93-2.77 (1 H, m), 3.18-3.02 (4 H, m), 3.32 (3 H,s), 4.26-4.05 (2 H, m), 6.47 (1 H, s), 6.93 (1 H, s), 7.09 (1 H, d, J =5.5 Hz), 7.17 (2 H, s), 7.45 (1 H, dd, J = 8.4, 1.2 Hz), 7.58 (1 H, s),8.00 (1 H, d, J = 8.4 Hz), 8.34 (1 H, d, J = 5.5 Hz), 8.97 (1 H, s)429.05 T8-63.11

1-(2- aminopyrimidin- 4-yl)-6-[3-hydroxy- 3-(3-methyl-1,2,4-oxadiazol-5-yl)but- 1-yn-1-yl]-N,N- dimethyl-1H-indazole- 3-carboxamide(500 MHz, DMSO) delta 1.95 (3 H, s), 2.37 (3 H, s), 3.09 (3 H, s),7.16-7.01 (3 H, m), 7.22 (1 H, s), 7.43 (1 H, dd, J = 8.4, 1.3 Hz), 8.01(1 H, d, J = 7.7 Hz), 8.33 (1 H, d, J = 5.6 Hz), 8.97 (1 H, s). 433.1T8-63.12

1-(2- aminopyrirnidin- 4-yl)-6-(2-{7-hydroxy- 5H,6H,7H-pyrrolo[1,2-a]imidazol- 7-yl}ethynyl)-N,N- dimethyl-1H-indazole- 3-carboxamide(500 MHz, DMSO) delta 2.79-2.88 (1 H, m), 3.07-3.19 (4 H, m), 3.32 (3 H,s), 3.99-4.15 (2 H, m), 6.60 (1 H, s), 7.01 (1 H, s), 7.05-7.22 (4 H,m), 7.43 (1 H, dd, J = 8.20, 1.42 Hz), 8.01 (1 H, d, J = 8.20 Hz), 8.34(1 H, d, J = 5.83 Hz), 8.96 (1 H, s) 429.15 T8-63.13

7-{2-[1- (2-aminopyrimidin- 4-yl)-3-[(morpholin- 4-yl)carbonyl]-1H-indazol-6- yl]ethynyl}-5H,6H,7H- pyrrolo[1,2-a] imidazol-7-ol (500MHz, DMSO) delta 2.78-2.91 (1 H, m), 3.06-3.19 (1 H, m), 3.66 (2 H, br.s.), 3.74 (4 H, d, J = 5.99 Hz), 3.94 (2 H, br. s.), 4.07- 4.15 (2 H,m), 6.60 (1 H, s), 7.00 (1 H, s), 7.07 (1 H, d, J = 5.52 Hz), 7.15 (2 H,s), 7.45 (1 H, d, J = 8.35 Hz), 8.03 (1 H, d, J = 8.35 Hz), 8.35 (1 H,d, J = 5.36 Hz), 8.97 (1 H, s) 471.1 T8-63.14

4-[1-(2- aminopyrimidin- 4-yl)-3-[(morpholin- 4-yl)carbonyl]-1H-indazol-6-yl]- 2-(pyrimidin-2-yl) but-3-yn-2-ol (250 MHz, DMSO) delta1.94 (3 H, s), 3.78- 3.59 (6 H, m), 4.00- 3.89 (2 H, m), 6.28 (1 H, s),7.09 (1 H, d, J = 5.5 Hz), 7.17 (2 H, s), 7.40 (1 H, dd, J = 8.4, 1.4Hz), 7.52 (1 H, t, J = 4.9 Hz), 8.01 (1 H, d, J = 8.4 Hz), 8.36 (1 H, d,J = 5.4 Hz), 9.15-8.68 (3 H, m). 471.05 T8-63.15

(2R)-4-[1-(2- aminopyrimidin- 4-yl)-3- [(morpholin-4-yl)carbonyl]indazol-6-yl]- 2-(5-methyl-1,2,4- oxadiazol-3-yl)but- 3-yn-2-ol(250 MHz, DMSO) delta 1.90 (3 H, s), 2.63 (3 H, s), 3.66 (2 H, br. s.),3.74 (4 H, s), 3.94 (2 H, br. s.), 6.81 (1 H, s), 7.07 (1 H, s), 7.16 (2H, br. s.), 7.44 (1 H, dd, J = 8.38, 1.22 Hz), 8.03 (1 H, d, J = 8.22Hz), 8.35 (1 H, d, J = 5.48 Hz), 8.95 (1 H, s) 475.05 T8-63.16

(2S)-4-[1-(2- aminopyrimidin- 4-yl)-3- [(morpholin-4-yl)carbonyl]indazol-6-yl]- 2-(5-methyl-1,2,4- oxadiazol-3-yl)but- 3-yn-2-ol(250 MHz, DMSO) delta 1.89 (3 H, s), 2.62 (3 H, s), 3.61-3.80 (6 H, m),3.92 (2 H, d, J = 3.65 Hz), 6.80 (1 H, s), 7.04-7.10 (1 H, m), 7.10-7.23(2 H, m), 7.43 (1 H, dd, J = 8.38, 1.22 Hz), 8.02 (1 H, d, J = 8.53 Hz),8.35 (1 H, d, J = 5.48 Hz), 8.95 (1 H, s) 475.1 T8-63.17

4-[1-(2- aminopyrimidin- 4-yl)-3-[(morpholin- 4-yl)carbonyl]-1H-indazol-6-yl]- 2-[5-(methoxymethyl)- 1,2-oxazol-3-yl] but-3-yn-2-ol(500 MHz, CDCl₃) delta 2.03 (3 H, s), 3.47 (3 H, s), 3.80 (2 H, d, J =4.10 Hz), 3.87 (2 H, d, J = 4.73 Hz), 3.91 (2 H, d, J = 4.10 Hz), 3.94-4.05 (1 H, m), 4.11 (2 H, br. s.), 4.57 (2 H, s), 5.39 (2 H, br. s.),6.49 (1 H, s), 7.21 (1 H, d, J = 5.36 Hz), 7.44 (1 H, d, J = 8.20 Hz),8.08 (1 H, d, J = 8.20 Hz), 8.34 (1 H, br. s.), 8.86 (1 H, s) 504.05T8-63.18

4-[1-(2- aminopyrimidin- 4-yl)-3-[(morpholin- 4-yl)carbonyl]-1H-indazol-6-yl]- 2-(1-methyl-1H-1,2,4- triazol-3-yl)but-3- yn-2-ol (500MHz, DMSO) delta 1.89 (3 H, s), 3.68- 3.64 (2 H, m), 3.77- 3.71 (4 H,m), 3.87 (3 H, s), 3.97-3.91 (2 H, m), 6.24 (1 H, s), 7.08 (1 H, d, J =5.5 Hz), 7.15 (2 H, s), 7.41 (1 H, dd, J = 8.4, 1.1 Hz), 8.01 (1 H, d, J= 8.4 Hz), 8.35 (1 H, d, J = 5.5 Hz), 8.42 (1 H, s), 8.91 (1 H, s).474.1 T8-63.19

4-[1-(2- aminopyrimidin- 4-yl)-3-[(morpholin- 4-yl)carbonyl]-1H-indazol-6-yl]- 2-(pyrimidin-4-yl) but-3-yn-2-ol (500 MHz, DMSO) delta1.86 (3 H, s), 3.61- 3.81 (6 H, m), 3.92 (2 H, s), 6.79 (1 H, s), 7.08(1 H, d, J = 5.36 Hz), 7.15 (2 H, br. s.), 7.42 (1 H, d, J = 8.51 Hz),7.86 (1 H, d, J = 5.20 Hz), 8.00 (1 H, d, J = 8.51 Hz), 8.34 (1 H, d, J= 4.89 Hz), 8.89 (1 H, d, J = 4.89 Hz), 8.93 (1 H, s), 9.21 (1 H, s)471.1 T8-63.20

4-[1-(2- aminopyrimidin- 4-yl)-3-[(morpholin- 4-yl)carbonyl]-1H-indazol-6-yl]- 1-fluoro-2- methylbut-3-yn-2-ol (500 MHz, MeOD) delta1.61 (3 H, d, J = 1.89 Hz), 3.71-3.80 (2 H, m), 3.81-3.92 (4 H, m),3.98-4.10 (2 H, m), 4.42 (2 H, d, J = 51.07 Hz), 7.21 (1 H, d, J = 5.67Hz), 7.45 (1 H, d, J = 7.09 Hz), 7.99 (1 H, d, J = 8.35 Hz), 8.29 (1 H,d, J = 5.67 Hz), 9.03 (1 H, s) 425.05 T8-63.21

4-[1-(2- aminopyrimidin- 4-yl)-3-[(morpholin- 4-yl)carbonyl]-1H-indazol-6-yl]- 1-fluoro-2- (fluoromethyl) but-3-yn-2-ol (500 MHz,DMSO) delta 3.57-3.83 (6 H, m), 3.93 (2 H, d, J = 4.10 Hz), 4.41-4.72 (4H, m), 6.70 (1 H, br. s.), 7.08 (1 H, d, J = 5.36 Hz), 7.19 (2 H, br.s.), 7.46 (1 H, d, J = 8.35 Hz), 8.04 (1 H, d, J = 8.35 Hz), 8.36 (1 H,d, J = 5.52 Hz), 9.00 (1 H, s) 443.05 T8-63.22

7-{2-[1-(2- aminopyrimidin- 4-yl)-3-[(morpholin- 4-yl)carbonyl]-1H-indazol-6- yl]ethynyl}-5H,6H,7H- cyclopenta[b] pyridin-7-ol (500 MHz,CDCl) delta 2.38-2.46 (1 H, m), 2.59-2.71 (1 H, m), 2.89-2.99 (1 H, m),3.00-3.09 (1 H, m), 3.66 (2 H, d, J = 4.26 Hz), 3.74 (4 H, d, J = 5.52Hz), 3.93 (2 H, br. s.), 6.28 (1 H, s), 7.07 (1 H, d, J = 5.36 Hz), 7.15(2 H, br. s.), 7.30 (1 H, dd, J = 7.49, 4.81 Hz), 7.41 (1 H, dd, J =8.43, 1.02 Hz), 7.75 (1 H, d, J = 7.57 Hz), 8.01 (1 H, d, J = 8.35 Hz),8.35 (1 H, d, J = 4.57 Hz), 8.47 (1 H, d, J = 3.78 Hz), 8.92 (1 H, s)482.15 T8-63.23

4-[1-(2- aminopyrimidin- 4-yl)-3-[(morpholin- 4-yl)carbonyl]-1H-indazol-6-yl]- 2-[5- (methoxymethyl)- 1,2-oxazol-3-yl] but-3-yn-2-ol(500 MHz. CDCl₃) delta 2.03 (3 H, s), 3.47 (3 H, s), 3.80 (2 H, d, J =4.10 Hz), 3.87 (2 H, d, J = 4.73 Hz), 3.91 (2 H, d, J = 4.10 Hz), 3.94-4.05 (1 H, m), 4.11 (2 H, br. s.), 4.57 (2 H, s), 5.39 (2 H, br. s.),6.49 (1 H, s), 7.21 (1 H, d, J = 5.36 Hz), 7.44 (1 H, d, J = 8.20 Hz),8.08 (1 H, d, J = 8.20 Hz), 8.34 (1 H, br. s.), 8.86 (1 H, s) 504.05

Example 64 Preparation of4-[1-(2-aminopyrimidin-4-yl)-3-[(pyrrolidin-1-yl)carbonyl]-1H-indazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

Step 1: Synthesis of 6-bromo-3-[(pyrrolidin-1-yl)carbonyl]-1H-indazole

The title compound was prepared by procedure described in Example 62-a,by substituting morpholine with pyrrolidine in Step 1: ¹H NMR (250 MHz,DMSO) delta 1.89 (4H, dt, J=18.24, 6.64 Hz), 3.56 (2H, t, J=6.62 Hz),3.93 (2H, t, J=6.47 Hz), 7.36 (1H, dd, J=8.60, 1.60 Hz), 7.84 (1H, d,J=1.37 Hz), 8.09 (1H, d, J=8.68 Hz); LC-MS: m/z=+293.85/295.75 (M+H)+.

Step 2—Synthesis of4-{6-bromo-3-[(pyrrolidin-1-yl)carbonyl]indazol-1-yl}pyrimidin-2-amine

The title compound was prepared by procedure described in Example 62-b,by substituting 6-bromo-3-[(morpholin-4-yl)carbonyl]-1H-indazole with6-bromo-3-[(pyrrolidin-1-yl)carbonyl]-1H-indazole in Step 2: ¹H NMR (250MHz, DMSO) delta 1.79-2.09 (4H, m), 3.60 (2H, t, J=6.47 Hz), 3.87-4.08(2H, m), 7.10 (1H, d, J=5.48 Hz), 7.20 (2H, br. s.), 7.59 (1H, dd,J=8.60, 1.29 Hz), 8.16 (1H, d, J=8.53 Hz), 8.35 (1H, d, J=5.48 Hz), 9.18(1H, s); LC-MS: m/z=+387.00/388.80 (M+H)+.

Step 3—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-3-[(pyrrolidin-1-yl)carbonyl]-1H-indazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

The title compound was prepared by procedure described in Example 62-c,by substituting1-(2-aminopyrimidin-4-yl)-6-bromo-N,N-dimethylindazole-3-carboxamidewith4-{6-bromo-3-[(pyrrolidin-1-yl)carbonyl]indazol-1-yl}pyrimidin-2-amineand 2-(1,3-thiazol-2-yl)but-3-yn-2-ol with2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol in Step 3: ¹H NMR (500 MHz,DMSO) delta 1.84-1.93 (5H, m), 1.93-1.98 (2H, m), 2.42 (3H, s), 3.60(2H, t, J=6.86 Hz), 3.99 (2H, t, J=6.78 Hz), 6.41 (1H, s), 6.57 (1H, s),7.13 (1H, d, J=5.36 Hz), 7.15 (2H, br. s.), 7.44 (1H, dd, J=8.43, 1.18Hz), 8.22 (1H, d, J=8.35 Hz), 8.36 (1H, d, J=5.52 Hz), 8.94 (1H, s);LC-MS: m/z=+458.45 (M+H)+.

Example 65 Preparation of1-(2-aminopyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl]-N-methy1-1H-indazole-3-carboxamide

Step 1—Synthesis of1-(2-aminopyrimidin-4-yl)-6-bromoindazole-3-carboxylic Acid

To suspension of 6-bromo-1H-indazole-3-carboxylic acid (5 g, 20.77 mmol)in DMF (40 mL) was added NaH (60%, 1.7 g, 41.5 mmol). The mixture wasstirred at RT for 10 min, followed by addition of4-chloro-pyrimidin-2-ylamine (4.0 g, 31 mmol). The mixture was heated at65° C. for 2 hr. The reaction cooled to RT, then another 1 eq NaH added(ca 0.78 g). Heating continued at 65° C. overnight. Reaction mixture wasallowed to cool to RT. The mixture was quenched by portionwise additionto water (10 mL) resulting in formation of a precipitate. The mixturewas acidified with 0.5M aq citric acid. The precipitate was collected bysuction filtration through a flitted sinter funnel and washed withMeOH/EtOAc (1/1) and was thoroughly dried under high vacuum to give thetitle compound as a beige solid (5.8 g, LC-MS purity=88%); LC-MS:m/z=+333.85/335.80 (M+H)+.

Step 2—Synthesis of1-(2-aminopyrimidin-4-yl)-6-bromo-N-methylindazole-3-carboxamide

To a solution of 1-(2-aminopyrimidin-4-yl)-6-bromoindazole-3-carboxylicacid (300 mg, 0.79 mmol) in DCM (2 mL), was added thionyl chloride (0.28mL, 3.9 mmol). DMF (0.01 mL) added

The mixture was stirred at RT for 1 hr. The mixture was cooled to RT,concentrated in vacuo, DCM (2 mL) added and concentration in vacuo wasrepeated. To this residue was added 2M methylamine in MeOH (2.0 mL, 3.95mmol). The resultant mixture stirred for 30 min, then concentrated invacuo and partitioned between EtOAc and water. The precipitate formedwas collected by suction filtration. The aqueous layer of the filtratewas extracted with more EtOAc. Combined organics dried (Na₂SO₄);filtered and concentrated in vacuo. This product was combined with theprecipitate collected to give the title compound (290 mg, LC-MSpurity=77%). LC-MS: m/z=+346.90/348.75 (M+H)+.

Step 3—Synthesis of1-(2-aminopyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl]-N-methy1-1H-indazole-3-carboxamide

The title compound was prepared by procedure described in Example 62-c,by substituting1-(2-aminopyrimidin-4-yl)-6-bromo-N,N-dimethylindazole-3-carboxamidewith 1-(2-aminopyrimidin-4-yl)-6-bromo-N-methylindazole-3-carboxamideand 2-(1,3-thiazol-2-yl)but-3-yn-2-ol with(2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol in Step 3: ¹H NMR (500MHz, DMSO) delta 1.87 (3H, s), 2.42 (3H, s), 2.87 (3H, d, J=4.73 Hz),6.42 (1H, s), 6.60 (1H, s), 7.17 (2H, br. s.), 7.32 (1H, d, J=5.36 Hz),7.46 (1H, dd, J=8.35, 1.10 Hz), 8.27 (1H, d, J=8.20 Hz), 8.40 (1H, d,J=5.36 Hz), 8.78 (1H, d, J=4.73 Hz), 8.94 (1H, s); LC-MS: m/z=+418.05(M+H)+.

Example 66 Preparation of1-(2-aminopyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl]-1H-indazole-3-carboxamide

Step 1—Synthesis of1-(2-aminopyrimidin-4-yl)-6-bromoindazole-3-carboxamide

To a solution of 1-(2-aminopyrimidin-4-yl)-6-bromoindazole-3-carboxylicacid (500 mg, 1.32 mmol) in DCM (5 mL), was added thionyl chloride (0.6mL, 7.9 mmol) followed by DMF (0.02 mL). The mixture was stirred at RTfor 1 hr. The mixture was concentrated in vacuo, DCM (2 mL) added andconcentration in vacuo was repeated. To this residue was added THF (5mL) and conc. aq NH₃ (0.5 mL). The mixture stirred for 30 min, thendiluted with water and the resultant solid was collected by suctionfiltration. The solid was thoroughly dried under high vacuum, to givethe title compound (360 mg): ¹H NMR (250 MHz, DMSO) delta 7.15 (1H, br.s.), 7.32 (1H, d, J=5.48 Hz), 7.60 (1H, dd, J=8.60, 1.60 Hz), 7.74 (1H,br. s.), 8.20 (1H, d, J=8.38 Hz), 8.38 (1H, d, J=5.48 Hz), 9.18 (1H, d,J=1.22 Hz); LC-MS: m/z=+332.90/334.70 (M+H)+.

Step 2—Synthesis of1-(2-aminopyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl]-1H-indazole-3-carboxamide

The title compound was prepared by procedure as described in Example62-c by reacting 1-(2-aminopyrimidin-4-yl)-6-bromoindazole-3-carboxamideand (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol: ¹H NMR (500 MHz,DMSO) delta 1.86 (3H, s), 2.42 (3H, s), 6.41 (1H, s), 6.59 (1H, s), 7.16(2H, br. s.), 7.34 (1H, d, J=5.52 Hz), 7.44 (1H, dd, J=8.43, 1.18 Hz),7.75 (1H, s), 8.21 (1H, s), 8.26 (1H, d, J=8.35 Hz), 8.38 (1H, d, J=5.52Hz), 8.93 (1H, s); LC-MS: m/z=+404 (M+H)+.

Example 67 Preparation of1-{[1-(2-aminopyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-yn-1-yl]-1H-indazol-3-yl]carbonyl}azetidin-3-ol

Step 1—Synthesis of1-{[1-(2-aminopyrimidin-4-yl)-6-bromoindazol-3-yl]carbonyl}azetidin-3-ol

To a solution of 1-(2-aminopyrimidin-4-yl)-6-bromoindazole-3-carboxylicacid (0.38 g, 1.12 mmol)) in DCM (5 mL), was added thionyl chloride(0.49 ml, 6.74 mmol) followed by a drop of DMF. The mixture was stirredat 40° C. overnight. The reaction mixture was concentrated in vacuo andDCM added and the concentration repeated (×2). The acid chlorideintermediate was suspended in DCM (10 ml), azetidin-3-ol hydrochloride(491.82 mg, 4.49 mmol) followed by DIPEA (0.86 ml, 4.94 mmol). Thereaction was stirred at RT for 0.5 hr and then concentrated in vacuo.The residue was diluted with more DCM and water and the organicsextracted (2×20 ml DCM). The combined organic layers were dried(Na₂SO₄), filtered and concentrated in vacuo to give the titleintermediate (214 mg, LC-MS purity=63%); LC-MS: m/z=+388.95/390.80(M+H)+.

Step 2-Synthesis of1-{[1-(2-aminopyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-yn-1-yl]-1H-indazol-3-yl]carbonyl}azetidin-3-ol

The title compound was prepared according to the procedure described inExample 62-c by reacting1-{[1-(2-aminopyrimidin-4-yl)-6-bromoindazol-3-yl]carbonyl}azetidin-3-oland (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol; ¹H NMR (500 MHz,CDCl₃) delta 1.93 (3H, s), 2.54 (3H, s), 4.01 (1H, dd, J=10.8, 3.8 Hz),4.42-4.35 (1H, m), 4.50-4.44 (1H, m), 4.63 (1H, dd, J=6.0, 4.5 Hz), 4.83(1H, dd, J=10.6, 6.7 Hz), 5.12 (1H, d, J=6.0 Hz), 5.65-5.54 (2H, m),5.76 (1H, s), 7.05 (1H, d, J=5.5 Hz), 7.33 (1H, dd, J=8.4, 1.2 Hz),8.33-8.10 (2H, m), 8.80 (1H, d, J=6.5 Hz); LC-MS: m/z=+461.1 (M+H)+.

Example 68 (i) and Example 68 (ii) Preparation of4-[1-(2-aminopyrimidin-4-yl)-3-{[cis-2,6-dimethylmorpholin-4-yl]carbonyl}-1H-indazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol[Example 68 (i)] and4-[1-(2-aminopyrimidin-4-yl)-3-{[(trans)-2,6-dimethylmorpholin-4-yl]carbonyl}-1H-indazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol[Example 68 (ii)]

Absolute stereochemistry to be assigned.

Step 1—Synthesis of4-{6-bromo-3-[(2,6-dimethylmorpholin-4-yl)carbonyl]indazol-1-yl}pyrimidin-2-amine

To a solution of 1-(2-aminopyrimidin-4-yl)-6-bromoindazole-3-carboxylicacid (0.38 g, 1.12 mmol)) in DCM (5 mL), was added thionyl chloride(0.49 ml, 6.74 mmol) followed by a drop of DMF. The mixture was stirredat 40° C. overnight. The reaction mixture was concentrated in vacuo andDCM added and the concentration repeated (×2). The acid chlorideintermediate was suspended in DCM (10 ml), 2,6-dimethylmorpholine (0.55ml, 4.49 mmol) added. The reaction was stirred at RT for 0.5 hr and thenconcentrated in vacuo. The residue was diluted with more DCM and waterand the organics extracted (2×20 ml). The combined organic layers weredried (Na₂SO₄), filtered and concentrated in vacuo. Crude materialpurified by column chromatography, (9:1 DCM: methanol, Rf=0.6). Elutionwith DCM:methanol 98:2 to 90:10 gave the mixture of cis and trans2,6-dimethylmorpholin-4-yl compound (200 mg): ¹H NMR (500 MHz, CDCl₃)delta 1.21 (3H, d, J=6.2 Hz), 1.30 (3H, d, J=6.1 Hz), 2.64 (1H, dd,J=13.1, 10.8 Hz), 2.99 (1H, dd, J=13.2, 10.6 Hz), 4.84-3.26 (6H, m),5.23 (2H, s), 7.23-7.19 (1H, m), 7.50 (1H, dd, J=8.6, 1.6 Hz), 7.98 (1H,d, J=8.6 Hz), 8.37 (1H, dd, J=5.6, 2.2 Hz), 9.01 (1H, d, J=1.2 Hz);LC-MS: m/z=+430.95/432.85 (M+H)+.

Step 2—Synthesis and separation of4-[1-(2-aminopyrimidin-4-yl)-3-{[cis-2,6-dimethylmorpholin-4-yl]carbonyl}-1H-indazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol[Example 68 (i)] and4-[1-(2-aminopyrimidin-4-yl)-3-{[(trans)-2,6-dimethylmorpholin-4-yl]carbonyl}-1H-indazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol[Example 68 (ii)]

To a pressure tube was added4-{6-bromo-3-[(2,6-dimethylmorpholin-4-yl)carbonyl]indazol-1-yl}pyrimidin-2-amine(170 mg, 0.39 mmol) followed by piperidine (1.0 mL),tetrakis(triphenylphosphine)palladium (45.55 mg, 0.04 mmol), copper(I)iodide (7.51 mg, 0.04 mmol) and 2-(pyrimidin-2-yl)but-3-yn-2-ol (116.8mg, 0.79 mmol) in more piperidine (1.0 mL). The reaction was capped andstirred at 65° C. for 1.5 h. The reaction mixture was concentrated invacuo after 1 hr 20 min. DCM (5 mL X²) was added and the mixture wasconcentrated in vacuo. Crude material was purified by columnchromatography (Biotage, DCM:methanol 98:2 to 90:10) to give the productas a mixture of cis and trans isomers. The isomeric mixture was thenseparated by reverse phase preparative HPLC (MeCN/Water+0.2% ammoniumhydroxide) to give Example 68 (i) and Example 68 (ii).

Example 68(i)

¹H NMR (500 MHz, CDCl₃) delta 1.19 (3H, d, J=6.2 Hz), 1.29 (3H, d, J=6.2Hz), 2.06 (3H, s), 2.68-2.57 (1H, m), 2.97 (1H, dd, J=13.3, 10.8 Hz),3.72 (2H, d, J=6.5, 4.0 Hz), 4.58 (1H, d, J=13.3 Hz), 4.68 (1H, d,J=13.2 Hz), 5.25 (2H, s), 5.36 (1H, s), 7.21 (1H, d, J=5.5 Hz), 7.35(1H, t, J=4.9 Hz), 7.42 (1H, dd, J=8.4, 1.2 Hz), 7.99 (1H, d, J=8.4 Hz),8.35 (1H, d, J=4.7 Hz), 8.85 (2H, d, J=4.9 Hz), 8.89 (1H, s); LC-MS:m/z=+499.1 (M+H)+.

Example 68 (ii)

¹H NMR (500 MHz, CDCl₃) 1.38-1.20 (6H, m), 2.05 (3H, s), 3.45 (1H, dd,J=13.1, 6.8 Hz), 3.87 (1H, dd, J=13.3, 5.5 Hz), 4.08-3.96 (2H, m), 4.13(2H, ddd, J=13.7, 8.1, 4.8 Hz), 5.80-4.93 (3H, m), 7.18 (1H, d, J=5.6Hz), 7.34 (1H, t, J=4.9 Hz), 7.42 (1H, dd, J=8.4, 1.1 Hz), 8.02 (1H, d,J=8.4 Hz), 8.34 (1H, d, J=5.3 Hz), 8.85 (2H, d, J=4.9 Hz), 8.88 (1H, s);LC-MS: m/z=+499.1 (M+H)+.

Example 69 Preparation and Chiral Separation of(7R)-7-{2-[1-(2-aminopyrimidin-4-yl)-3-[(morpholin-4-yl)carbonyl]indazol-6-yl]ethynyl}-5H,6H-cyclopenta[b]pyridin-7-ol[Example 69(i)] and(7S)-7-{2-[1-(2-aminopyrimidin-4-yl)-3-[(morpholin-4-yl)carbonyl]indazol-6-yl]ethynyl}-5H,6H-cyclopenta[b]pyridin-7-ol[Example 69(ii)]

To a pressure tube was added4-{6-bromo-3-[(morpholin-4-yl)carbonyl]indazol-1-yl}pyrimidin-2-amine(150 mg, 0.37 mmol) followed by piperidine (2.0 mL),tetrakis(triphenylphosphine)palladium (42.99 mg, 0.037 mmol), copper(I)iodide (7.1 mg, 0.037 mmol) and7-ethynyl-5H,6H-cyclopenta[b]pyridin-7-ol (118.43 mg, 0.74 mmol). Thereaction was capped and stirred at 65° C. for 2.5 hr. The reactionmixture was concentrated in vacuo. DCM (5 mL X²) added and the mixturewas concentrated in vacuo. The crude material was purified by columnchromatography (elution with 99:1 to 90:10 DCM: methanol) to give aresidue which was triturated with MeCN/diethyl ether (3:1), giving theracemic product.

The enantiomers were separated using the following method. Instrument:Gilson 215 Liquid Handler, 2× Gilson 306 Pumps, Gilson 805 ManometricModule, Gilson 119 UV/Vis Dual Detector. Flow rate: 18 ml/min. MobilePhase:Methanol+0.1% DEA. Column: Chiralcel OJ, 25 cm. Particle Size: 10μm. Loading: 1.5 ml (<2 mg).

The first peak eluted gave(7R)-7-{2-[1-(2-aminopyrimidin-4-yl)-3-[(morpholin-4-yl)carbonyl]indazol-6-yl]ethynyl}-5H,6H-cyclopenta[b]pyridin-7-ol(Example 69(i)): ¹H NMR (500 MHz, DMSO) delta 2.43 (1H, ddd, J=13.04,8.00, 4.81 Hz), 2.60-2.70 (1H, m), 2.89-3.00 (1H, m), 3.00-3.10 (1H, m),3.61-3.69 (2H, m), 3.74 (4H, d, J=5.52 Hz), 3.93 (2H, d, J=4.41 Hz),6.30 (1H, br. s.), 7.08 (1H, d, J=5.52 Hz), 7.15 (2H, br. s.), 7.31 (1H,dd, J=7.65, 4.81 Hz), 7.38-7.48 (1H, m), 7.76 (1H, d, J=7.41 Hz), 8.01(1H, d, J=8.35 Hz), 8.35 (1H, d, J=5.52 Hz), 8.47 (1H, d, J=4.57 Hz),8.92 (1H, s); LC-MS: m/z=+482.15 (M+H)+.

The second peak eluted gave(7S)-7-{2-[1-(2-aminopyrimidin-4-yl)-3-[(morpholin-4-yl)carbonyl]indazol-6-yl]ethynyl}-5H,6H-cyclopenta[b]pyridin-7-ol(Example 69(ii)): ¹H NMR (500 MHz, DMSO) delta 2.19-2.27 (1H, m),2.43-2.52 (1H, m), 2.71-2.81 (1H, m), 2.81-2.90 (1H, m), 3.48 (2H, d,J=4.57 Hz), 3.55 (4H, d, J=5.52 Hz), 3.74 (2H, d, J=4.41 Hz), 6.89 (1H,d, J=5.52 Hz), 7.12 (1H, dd, J=7.57, 4.89 Hz), 7.23 (1H, d, J=8.35 Hz),7.57 (1H, d, J=7.41 Hz), 7.82 (1H, d, J=8.20 Hz), 8.16 (1H, d, J=5.52Hz), 8.28 (1H, d, J=4.57 Hz), 8.74 (1H, s); LC-MS: m/z=+482.15 (M+H)+.

Absolute stereochemistry to be assigned.

Example 70 Preparation of4-[1-(2-aminopyrimidin-4-yl)-3-[(morpholin-4-yl)carbonyl]-1H-indazol-6-yl]-2-(1,3-oxazol-2-yl)but-3-yn-2-ol

Step 1: Synthesis of4-{6-iodo-3-[(morpholin-4-yl)carbonyl]indazol-1-yl}pyrimidin-2-amine

To a solution of 1-(2-aminopyrimidin-4-yl)-6-iodoindazole-3-carboxylicacid (3 g, 7.87 mmol)) in DCM (40 mL), was added thionyl chloride (6.85ml, 94.46 mmol) followed by DMF (catalytic, 3 drops). The mixture wasstirred at 50° C. for 1 hour. The reaction mixture was concentrated invacuo and DCM added and the concentration repeated (×2). The crude acidchloride (assumed 7.87 mmol) was suspended in more DCM (30 mL) andmorpholine (1.37 ml, 15.74 mmol) was added at 0° C. dropwise. Thereaction was stirred at RT overnight. The reaction mixture was dilutedwith more DCM (25 ml) and 2M Na₂CO₃ added (35 ml). A pale brownprecipitate was collected by filtration and washed with more DCM. Theprecipitate was slurried in water:acetonitrile (3:1, 10 ml) and theoff-white solid collected by filtration and washed with morewater:acetonitrile (3:1, 2×1 ml). The solid was then dried under vacuumto give the title compound (2.72 g, LC-MS purity=86%): ¹H NMR (500 MHz,DMSO) delta 3.41-3.76 (6H, m), 3.85-3.97 (2H, m), 7.05 (1H, d, J=5.5Hz), 7.18 (2H, s), 7.74 (1H, dd, J=8.4, 1.1 Hz), 7.80 (1H, d, J=8.4 Hz),8.34 (1H, d, J=5.5 Hz), 9.33 (1H, s); LC-MS: m/z=+450.90 (M+H)+.

Step 2—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-3-[(morpholin-4-yl)carbonyl]-1H-indazol-6-yl]-2-(1,3-oxazol-2-yl)but-3-yn-2-ol

To a pressure tube was added4-{6-iodo-3-[(morpholin-4-yl)carbonyl]-1H-indazol-1-yl}pyrimidin-2-amine(150 mg, 0.33 mmol) followed by piperidine (2.0 mL),tetrakis(triphenylphosphine)palladium(0) (38.5 mg, 0.03 mmol), copper(I)iodide (6.35 mg, 0.03 mmol) and 2-(1,3-oxazol-2-yl)but-3-yn-2-ol (68.53mg, 0.5 mmol). The reaction was capped and stirred at 35° C. for 2.5 hr.The reaction mixture was concentrated in vacuo. DCM (5 mL×2) added andthe mixture was concentrated in vacuo. Purification by columnchromatography (1% to 10% MeOH in DCM), followed by trituration with amixture of MeCN/diethyl ether mixture (3/1) gave the title compound asan off-white solid (62 mg): ¹H NMR (500 MHz, DMSO) delta 3.67 (2H, d,J=4.26 Hz), 3.75 (4H, d, J=5.67 Hz), 3.94 (2H, d, J=3.94 Hz), 4.06 (3H,s), 6.72-6.89 (1H, m), 6.93-7.33 (4H, m), 7.45 (1H, d, J=7.57 Hz), 8.04(1H, d, J=7.88 Hz), 8.11-8.23 (1H, m), 8.97 (1H, s); LC-MS: m/z=+460.15(M+H)+.

Example 71 Preparation of1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]-N-methyl-N-(pyridin-2-yl)-1H-indazole-3-carboxamide

Step 1—Synthesis of 1-(2-aminopyrimidin-4-yl)-6-iodoindazole-3-carbonylchloride

To a solution of 1-(2-aminopyrimidin-4-yl)-6-iodoindazole-3-carboxylicacid (1.00 g, 2.62 mmol) in DCM (10 mL), was added thionyl chloride (1.9ml, 26.24 mmol)) followed by a drop of DMF. The mixture was stirred at50° C. for 45 minutes. The reaction mixture was concentrated in vacuoand DCM (5 mL) was added and the concentration repeated (×2). The crudeacid chloride was used directly in the next step: LC-MS m/z=+395.95(M+H)+(after conversion to methyl ester derivative)

Step 2—Synthesis of1-(2-aminopyrimidin-4-yl)-6-iodo-N-methyl-N-(pyridin-2-yl)indazole-3-carboxamide

To a solution of 1-(2-aminopyrimidin-4-yl)-6-iodoindazole-3-carbonylchloride (330 mg, 0.83 mmol) in DCM (5 mL) was addedN-methylpyridin-2-amine (0.1 ml, 0.99 mmol) followed by triethylamine(0.29 ml, 2.06 mmol). The reaction was stirred at RT overnight and thenconcentrated in vacuo. The residue was diluted with water (10 ml) andextracted with DCM (2×20 ml). The title intermediate was obtained as aprecipitate which was collected by suction filtration. The combinedorganic layers were dried (Na₂SO₄), filtered and concentrated in vacuo.The precipitate and organic extracts were combined to give the crudetitle intermediate; LC-MS purity=79%: ¹H NMR (500 MHz, DMSO) delta 3.54(3H, s), 6.28 (1H, d, J=5.5 Hz), 7.15 (2H, s), 7.25 (1H, dd, J=6.7, 5.0Hz), 7.40 (1H, d, J=8.1 Hz), 7.74 (1H, dd, J=8.5, 1.3 Hz), 7.79-7.84(2H, m), 8.19 (1H, d, J=5.5 Hz), 8.32 (1H, dd, J=4.6, 1.5 Hz), 9.24 (1H,s); LC-MS: m/z=+472.00 (M+H)+.

Step 3—Synthesis of1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]-N-methyl-N-(pyridin-2-yl)-1H-indazole-3-carboxamide

The title compound was prepared according to the procedure described inExample 70-b, by substituting4-{6-iodo-3-[(morpholin-4-yl)carbonyl]-1H-indazol-1-yl}pyrimidin-2-aminewith1-(2-aminopyrimidin-4-yl)-6-iodo-N-methyl-N-(pyridin-2-yl)indazole-3-carboxamideand 2-(1,3-oxazol-2-yl)but-3-yn-2-ol with2-(pyrimidin-2-yl)but-3-yn-2-ol in Step 2: ¹H NMR (500 MHz, DMSO) delta1.91 (3H, s), 3.54 (3H, s), 6.25 (1H, s), 6.28 (1H, d, J=5.5 Hz), 7.10(2H, s), 7.25 (1H, dd, J=6.9, 5.1 Hz), 7.37 (1H, dd, J=8.4, 1.0 Hz),7.41 (1H, d, J=8.1 Hz), 7.50 (1H, t, J=4.9 Hz), 7.80 (1H, td, J=7.8, 1.8Hz), 8.00 (1H, d, J=8.4 Hz), 8.19 (1H, d, J=5.4 Hz), 8.32 (1H, d, J=3.4Hz), 8.80 (1H, s), 8.86-8.96 (2H, m); LC-MS: m/z=+492.15 (M+H)+.

Example 72 Preparation of1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]-N-(pyridin-3-yl)-1H-indazole-3-carboxamide

The title compound was prepared according to the procedure described forthe preparation of1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]-N-methyl-N-(pyridin-2-yl)-1H-indazole-3-carboxamide(Example 71-c); ¹H NMR (500 MHz, DMSO) delta 1.94 (3H, s), 6.29 (1H, s),7.21 (2H, s), 7.42-7.57 (4H, m), 8.24-8.33 (2H, m), 8.38 (1H, d, J=3.9Hz), 8.45 (1H, d, J=5.3 Hz), 8.91 (2H, d, J=4.9 Hz), 8.96 (1H, s), 9.04(1H, s), 10.78 (1H, s); LC-MS: m/z=+478.1 (M+H)+.

Example 73 Preparation of1-{[1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(1,3-oxazol-2-yl)but-1-yn-1-yl]indazol-3-yl]carbonyl}azetidin-3-ol

Step 1 Synthesis of1-{[1-(2-aminopyrimidin-4-yl)-6-iodo-1H-indazol-3-yl]carbonyl}azetidin-3-ol

To a solution of1-(2-amino-pyrimidin-4-yl)-6-iodo-1H-indazole-3-carboxylic acid (500 mg,1.08 mmol) in DMF (5 ml) was added HATU (823.46 mg, 2.17 mmol) followedby azetidin-3-ol HCl (237.26 mg, 2.17 mmol) and triethylamine (0.45 ml,3.25 mmol). The reaction mixture was stirred at RT for 3 hr. A whiteprecipitate was also observed which was not soluble in EtOAc and water.The solid was filtered and washed with EtOAc and the filtrate worked up.The solid was dried and analysed by LCMS found to be clean titlecompound. To the filtrate water (6 ml) was added and the productextracted into EtOAc (2×10 ml). The combined organics were washed withwater and brine and concentrated in vacuo. The material was thenpurified by column chromatography, (9:1 DCM: methanol,). The combinedcolumn fractions were then triturated from acetonitrile to give thetitle compound; ¹H NMR (500 MHz, DMSO) 3.86 (1H, dd, J=10.56, 3.94 Hz),4.26-4.46 (2H, m), 4.52-4.64 (1H, m), 4.88 (1H, dd, J=9.77, 7.25 Hz),5.83 (1H, d, J=6.62 Hz), 7.10 (1H, d, J=5.36 Hz), 7.17 (2H, br. s), 7.77(1H, d, J=8.51 Hz), 8.04 (1H, d, J=8.51 Hz), 8.36 (1H, d, J=5.67 Hz),9.34 (1H, s). LC-MS: m/z=+436.95 (M+H)+.

Step 2 Synthesis of1-{[1-(2-aminopyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]-1H-indazol-3-yl]carbonyl}azetidin-3-ol

To a pressure tube was added1-{[1-(2-aminopyrimidin-4-yl)-6-iodo-1H-indazol-3-yl]carbonyl}azetidin-3-ol(150 mg, 0.34 mmol) followed by piperidine (2.0 mL), Pd(PPh₃)₄ (39.74mg, 0.03 mmol), copper(I) iodide (6.5 mg, 0.03 mmol) and2-(1,3-oxazol-2-yl)but-3-yn-2-ol (70.74 mg, 0.5 mmol). The reactionvessel was capped and stirred at 35° C. for 2.5 hr. The reaction mixturewas concentrated in vacuo. DCM (5 mL×2) added and the mixture wasconcentration in vacuo. The crude material purified by columnchromatography (elution with 1-10% MeOH in DCM) and was then trituratedfrom a MeCN/Ether mixture (3:1) to give the title compound: ¹H NMR(DMSO-d6, 500 MHz) delta 1.94 (3H, s), 3.87 (1H, dd, J=10.4, 3.9 Hz),4.31-4.44 (2H, m), 4.51-4.64 (1H, m), 4.88 (1H, dd, J=9.9, 6.9 Hz), 5.83(1H, d, J=6.5 Hz), 6.81 (1H, s), 7.12 (1H, d, J=5.5 Hz), 7.18 (2H, s),7.24 (1H, s), 7.46 (1H, d, J=8.4 Hz), 8.16 (1H, s), 8.27 (1H, d, J=8.4Hz), 8.37 (1H, d, J=5.5 Hz), 8.96 (1H, s). LC-MS: m/z+388.05 (M+H)+.

Example 74 Preparation of(2S)-4-[1-(2-aminopyrimidin-4-yl)-3-[(morpholin-4-yl)carbonyl]-1H-indazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol

To solution of4-{6-iodo-3-[(morpholin-4-yl)carbonyl]-1H-indazol-1-yl}pyrimidin-2-amine(60 mg, 0.13 mmol) in triethylamine (2 mL) was introducedtetrakis(triphenylphosphine)palladium (0) (15.4 mg, 0.01 mmol),copper(I) iodide (2.5 mg, 0.01 mmol) and(2S)-2-(pyrimidin-2-yl)but-3-yn-2-ol (30 mg, 0.20 mmol). After 18 hr atRT, the reaction mixture was concentrated in vacuo, DCM (10 mL) wasadded and the solution re-evaporated to dryness in vacuo (re-evaporationprocess repeated twice). Purification of the residue by columnchromatography (Biotage, DCM containing a 0-10% gradient of methanol)furnished the title compound as an off-white solid: ¹H NMR (500 MHz,DMSO-d6) delta 1.79-2.05 (3H, m), 3.59-3.68 (2H, m), 3.71-3.79 (4H, m),3.89-4.01 (2H, m), 6.17-6.37 (1H, m), 6.98-7.10 (1H, m), 7.12-7.27 (2H,m), 7.32-7.42 (1H, m), 7.47-7.58 (1H, m), 7.92-8.05 (1H, m), 8.26-8.39(1H, m), 8.80-9.04 (3H, m); LC-MS: m/z=+471.05 (M+H)+.

Example 75 Preparation of(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-[(morpholin-4-yl)carbonyl]-1H-indazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol

Title compound prepared and purified according to procedure describedfor(2S)-4-[1-(2-aminopyrimidin-4-yl)-3-[(morpholin-4-yl)carbonyl]-1H-indazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol(Example 74) to furnish the title compound as an off-white solid: ¹H NMR(500 MHz, DMSO-d6) delta 1.86-2.00 (3H, m), 3.58-3.69 (2H, m), 3.69-3.82(4H, m), 3.87-4.02 (2H, m), 6.17-6.31 (1H, m), 7.03-7.09 (1H, m),7.10-7.27 (2H, m), 7.34-7.45 (1H, m), 7.47-7.58 (1H, m), 7.90-8.04 (1H,m), 8.27-8.41 (1H, m), 8.82-8.97 (3H, m); LC-MS: m/z=+471.05 (M+H)+.

Example 76 Preparation of(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-[(4-fluoropiperidin-1-yl)carbonyl]-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-olmono-formate Salt

Step 1—Synthesis of1-(2-aminopyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-yn-1-yl]-1H-indazole-3-carboxylicAcid

To a solution of1-(2-aminopyrimidin-4-yl)-6-iodo-1H-indazole-3-carboxylic acid (150 mg,0.39 mmol) in piperidine (1.5 mL) was introducedtetrakis(triphenylphosphine)palladium (0) (45.5 mg, 0.04 mmol),copper(I) iodide (7.4 mg, 0.04 mmol) and(2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (120 mg, 0.79 mmol).The reaction was warmed to 35° C. for 1 hr. After cooling to RT, thereaction mixture was concentrated in vacuo and the residue purified bysilica gel flash column chromatography (eluent: DCM containing a 1-15%MeOH gradient followed by 85:15 DCM:7M ammonia in methanol). Thepartially purified product was suspended in 2M aqueous citric acid (3mL) and extracted with 3:1 chlorofolin/isopropanol (5×5 mL). Thecombined extracts were dried (Na₂SO₄), filtered and concentrated invacuo to furnish the title compound as a yellow-brown solid: ¹H NMR (500MHz, DMSO) delta 1.91 (3H, s), 2.64 (3H, s), 6.81 (1H, s), 7.27 (1H, d,J=5.9 Hz), 7.54 (1H, dd, J=8.4, 1.2 Hz), 7.80 (2H, s), 8.22 (1H, d,J=8.3 Hz), 8.42 (1H, d, J=6.0 Hz), 8.97 (1H, s), 13.92 (1H, s); LC-MS:m/z=+406.00 (M+H)+.

Step 2 Synthesis of(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-[(4-fluoropiperidin-1-yl)carbonyl]-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-olMono-Formate Salt

To a solution of1-(2-aminopyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-yn-1-yl]-1H-indazole-3-carboxylicacid (50 mg, 0.12 mmol) in DMF (3 mL) was introducedO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (94 mg, 0.25 mmol), 4-fluoropiperidine hydrochloride(22 mg, 0.16 mmol) and triethylamine (0.05 mL, 0.37 mmol). After 30minutes at RT, the reaction mixture was diluted with water (2 ml) andextracted with EtOAc (2×5 mL extractions). The combined organic extractswere washed with water (5 mL) and brine (5 ml), dried (Na₂SO₄), filteredand concentrated in vacuo. The residue was purified by silica gel flashcolumn chromatography (DCM containing a 2-10% gradient of methanol).Further purification by reverse phase preparative HPLC furnished thetitle compound as a mono-formate salt: ¹H NMR (500 MHz, CDCl₃) delta2.20-1.67 (7H, m), 2.65 (3H, s), 3.78-3.64 (1H, m), 3.96-3.80 (1H, m),4.25-4.06 (2H, m), 5.09-4.90 (1H, m), 6.42 (2H, s), 7.15 (1H, d, J=5.8Hz), 7.37 (1H, d, J=8.4 Hz), 7.97 (1H, d, J=8.3 Hz), 8.30-8.12 (2H, m),8.74 (1H, d, J=4.4 Hz); LC-MS: m/z=+491.10 (M+H)+.

Example 77 Preparation of4-[1-(2-aminopyrimidin-4-yl)-3-({2-oxa-6-azaspiro[3.3]heptan-6-yl}carbonyl)-1H-indazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol

Step 1-Synthesis of1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]indazole-3-carboxylicAcid

To a pressure tube containing1-(2-aminopyrimidin-4-yl)-6-iodoindazole-3-carboxylic acid (550 mg, 1.44mmol), copper(I) iodide (27.48 mg, 0.14 mmol),bis(triphenylphosphine)palladium(II) chloride (101.29 mg, 0.14 mmol) intriethylamine (4 mL) and THF (4 mL), was added2-(pyrimidin-2-yl)but-3-yn-2-ol (427.62 mg, 2.89 mmol). The reaction wassealed and stirred at 55° C. for 1 hr. The reaction mixture wasconcentrated in vacuo and the crude product was purified by columnchromatography (Biotage, 5-10% methanol in DCM followed by 10-20% [7MNH₃ in methanol] in DCM) to give the title intermediate as anorange/brown oil: ¹H NMR (250 MHz, DMSO) delta 1.92 (3H, s), 6.27 (1H,s), 6.98 (3H, s), 7.09 (1H, d, J=5.5 Hz), 7.26 (1H, d, J=9.5 Hz), 7.50(1H, t, J=4.9 Hz), 8.20-8.41 (3H, m), 8.73-9.02 (2H, m); LC-MS:m/z=+402.00 (M+H)+.

Step 2—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-3-({2-oxa-6-azaspiro[3.3]heptan-6-yl}carbonyl)-1H-indazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol

To a solution of1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]indazole-3-carboxylic acid (100 mg, 0.25 mmol) in DMF (2 ml) was added HATU (189.46 mg,0.5 mmol) followed by 2-oxa-6-azaspiro[3.3]heptane oxalate (94.26 mg,0.5 mmol) and triethylamine (0.1 ml, 0.75 mmol). The reaction mixturewas stirred at RT for 16 hr. Water (2 ml) was added to the reactionmixture and the product extracted into EtOAc (2×5 ml). The combinedorganics were washed with water (3 mL) and brine (3 mL) and concentratedin vacuo. The crude product was purified twice by flash chromatography(Biotage, 2-12% methanol in DCM) to give the title compound: ¹H NMR (500MHz, DMSO) delta 1.93 (3H, s), 4.31 (2H, s), 4.74 (4H, q, J=6.9 Hz),4.87 (2H, s), 6.26 (1H, s), 7.02-7.32 (3H, m), 7.41 (1H, dd, J=8.4, 1.2Hz), 7.51 (1H, t, J=4.9 Hz), 8.23 (1H, d, J=8.0 Hz), 8.39 (1H, d, J=5.5Hz), 8.75-9.10 (3H, m); LC-MS: m/z=+483.10 (M+H)+.

Example 78

Examples in Table 9 were prepared by procedure described in Example 77-bby reacting1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]indazole-3-carboxylic acid with the appropriate amine

TABLE 9 MS No. Structure Name 1H NMR (M + H) T9-78.1

4-[1-(2-aminopyrimidin- 4-yl)-3-{[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan- 5-yl]carbonyl}-1H-indazol-6-yl]-2-(pyrimidin-2-yl)but- 3-yn-2-ol (500 MHz, DMSO) delta 1.81-2.02(5H, m), 3.59 (1H, d, J = 10.7 Hz), 3.82 (1H, s), 3.90-3.95 (1H, m),3.99 (1H, q, J = 11.2 Hz), 4.71 (1H, d, J = 6.8 Hz), 5.02-5.59 (1H, m),6.26 (1H, s), 7.10 (1H, dd, J = 20.8, 5.5 Hz), 7.16 (2H, s), 7.40 (1H,ddd, J = 8.4, 2.8, 1.3 Hz), 7.51 (1H, t, J = 4.9 Hz), 8.10- 8.30 (1H,m), 8.35 (1H, dd, J = 5.4, 3.7 Hz), 8.77- 8.99 (3H, m) 483.1  T9-78.2

4-[1-(2-aminopyrimidin-4-yl)- 3-[(4-methylpiperazin-1-yl)carbonyl]-1H-indazol-6- yl]-2-(pyrimidin-2-yl)but-3- yn-2-ol (DMSO,500 MHz) delta 1.93 (3H, s), 2.22 (3H, s), 2.37-2.44 (4H, m), 3.71-3.78(2H, m), 3.80- 3.88 (2H, m), 6.28 (1H, s), 7.06 (1H, d, J = 5.5 Hz),7.15 (2H, s), 7.38 (1H, d, J = 9.6 Hz), 7.51 (1H, t, J = 4.9 Hz), 7.95(1H, d, J = 8.4 Hz), 8.35 (1H, d, J = 5.5 Hz), 8.82- 9.01 (3H, m) 484.15T9-78.3

1-(2-aminopyrimidin-4-yl)- N-(cyanomethyl)-6-[3- hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]-1H-indazole- 3-carboxamide; formic acid (DMSO, 500MHz) delta 1.93 (3H, s), 4.41 (2H, d, J = 5.7 Hz), 6.28 (1H, s), 7.19(2H, s), 7.31 (1H, d, J = 5.5 Hz), 7.44 (1H, dd, J = 8.4, 1.2 Hz), 7.51(1H, t, J = 4.9 Hz), 8.24 (1H, d, J = 8.5 Hz), 8.42 (1H, d, J = 5.5 Hz),8.71-9.06 (3H, m), 9.52 (1H, t, J = 5.7 Hz) 440.05 T9-78.4

1-(2-aminopyrimidin-4-yl)- 6-[3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]-N- (2-methoxyethyl)-N- methyl-1H-indazole-3-carboxamide; formic acid (DMSO, 250 MHz) delta 1.98 (3H, s), 3.23-3.33(6H, m), 3.65 (2H, t, J = 5.7 Hz), 3.85 (2H, t, J = 5.6 Hz), 5.76 (1H,s), 6.73 (2H, s), 7.11 (1H, d, J = 5.5 Hz), 7.39 (1H, dd, J = 8.4, 1.3Hz), 7.49 (1H, t, J = 4.9 Hz), 7.99 (1H, dd, J = 8.3, 0.7 Hz), 8.36 (1H,d, J = 5.5 Hz), 8.78- 8.96 (3H, m) 473.15 T9-78.5

4-[1-(2-aminopyrimidin-4-yl)- 3-[(3,3-difluoroazetidin-1-yl)carbonyl]-1H-indazol-6-yl]- 2-(pyrimidin-2-yl)but-3- yn-2-ol; formicacid (DMSO, 500 MHz) delta 1.92 (3H, s), 4.59 (2H, t, J = 12.2 Hz), 5.14(2H, t, J = 12.3 Hz), 6.27 (1H, s), 7.10-7.29 (3H, m), 7.43 (1H, dd, J =8.4, 1.2 Hz), 7.51 (1H, t, J = 4.9 Hz), 8.24 (1H, d, J = 8.6 Hz), 8.36(1H, d, J = 5.5 Hz), 8.85-9.03 (3H, m) 477.1  T9-78.6

4-[1-(2-aminopyrimidin-4-yl)- 3-({3-azabicyclo[3.1.0]hexan-3-yl}carbonyl)-1H-indazol-6- yl]-2-(pyrimidin-2-yl)but-3- yn-2-ol;formic acid (DMSO, 500 MHz) delta 0.16 (1H, q, J = 4.2 Hz), 0.69-0.80(1H, m), 1.58- 1.67 (1H, m), 1.68-1.77 (1H, m), 1.92 (3H, s), 3.57 (1H,dd, J = 12.1, 4.4 Hz), 3.95 (1H, d, J = 12.2 Hz), 4.01 (1H, dd, J =11.6, 4.3 Hz), 4.25 (1H, d, J = 11.5 Hz), 6.26 (1H, s), 7.04-7.23 (3H,m), 7.38 (1H, dd, J = 8.4, 1.3 Hz), 7.50 (1H, t, J = 4.9 Hz), 8.03-8.19(1H, m), 8.36 (1H, d, J = 5.5 Hz), 8.90 (3H, d, J = 4.8 Hz) 467.1 T9-78.7

l-{[1-(2-aminopyrimidin-4- yl)-6-[3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]-1H-indazol- 3-yl]carbonyl}piperidin-3-ol (500 MHz,DMSO) delta 1.42-1.55 (2H, m), 1.73- 1.89 (2H, m), 1.93 (3H, s),2.96-3.06 (1H, m), 3.54-3.65 (1H, m), 3.86- 4.31 (2H, m), 4.74-5.13 (1H,m), 6.28 (1H, s), 7.07 (1H, dd, J = 16.7, 5.5 Hz), 7.15 (2H, s), 7.38(1H, dd, J = 8.4, 1.2 Hz), 7.52 (1H, t, J = 4.9 Hz), 7.93 (1H, d, J =8.1 Hz), 8.35 (1H, d, J = 5.5 Hz), 8.74-9.20 (3H, m) 485.1  T9-78.8

1-{[1-(2-aminopyrimidin-4-yl)- 6-[3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]-1H-indazol- 3-yl]carbonyl}azetidin-3-ol; formic acid(500 MHz, DMSO) delta 1.93 (3H, s), 3.87 (1H, dd, J = 11.1, 3.4 Hz),4.23- 4.47 (2H, m), 4.53-4.66 (1H, m), 4.88 (1H, dd, J = 9.3, 6.9 Hz),5.83 (1H, d, J = 6.4 Hz), 6.27 (1H, s), 7.04-7.22 (3H, m), 7.41 (1H, dd,J = 8.4, 1.2 Hz), 7.51 (1H, t, J = 4.9 Hz), 8.24 (1H, d, J = 8.3 Hz),8.37 (1H, d, J = 5.5 Hz), 8.84-8.93 (3H, m) 466.05 T9-78.9

1-{[1-(2-aminopyrimidin-4-yl)-6- [3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]-1H-indazol-3- yl]carbonyl}azetidine-3-carbonitrile (500 MHz,DMSO) delta 1.93 (3H, s), 3.88-4.01 (1H, m), 4.28-4.36 (1H, m), 4.44(1H, t, J = 9.6 Hz), 4.86-4.94 (1H, m), 4.97 (1H, t, J = 9.4 Hz), 7.27(1H, d, J = 5.7 Hz), 7.45 (1H, d, J = 8.4 Hz), 7.51 (1H, t, J = 4.9 Hz),7.67 (2H, s), 8.24 (1H, d, J = 8.3 Hz), 8.38 (1H, d, J = 5.9 Hz),8.75-9.00 (3H, m) 457.1  T9-78.10

1-(2-aminopyrimidin-4-yl)-6-[3- hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]-N-(oxetan-3-yl)-1H- indazole-3-carboxamide; formic acid (500MHz, DMSO) delta 1.99 (3H, s), 4.77 (2H, t, J = 6.5 Hz), 4.87 (2H, t, J= 7.0 Hz), 5.19 (1H, q, J = 7.0 Hz), 7.42 (2H, s), 7.48 (1H, dd, J =8.3, 1.2 Hz), 7.53 (1H, d, J = 5.6 Hz), 7.57 (1H, t, J = 4.8 Hz), 8.27(1H, d, J = 8.3 Hz), 8.49 (1H, d, J = 5.7 Hz), 8.89-9.01 (3H, m), 9.57(1H, d, J = 7.1 Hz) 457.1 

Example 79 Preparation of1-(2-aminopyrimidin-4-yl)-6-{3-hydroxy-3-[5-(hydroxymethyl)-1,2-oxazol-3-yl]but-1-yn-1-yl}-N,N-dimethyl-1H-indazole-3-carboxamide

Step 1—Synthesis of 1-[5-(hydroxymethyl)-1,2-oxazol-3-yl]ethanone

A mixture of 2-(prop-2-yn-1-yloxy)tetrahydro-2H-pyran (0.5 ml, 3.57mmol) and iron(III) nitrate hydrate (0.86 ml, 3.57 mmol) in acetone (12mL) was stirred at 55° C. for 15 hr. The reaction mixture was cooled,filtered through a pad of Celite® and EtOAc (50 mL) was added. Theorganics were then washed with saturated NaHCO₃ solution (2×5 mL),saturated brine solution (5 mL) and water (5 mL) and then dried (Na₂SO₄)and concentrated in vacuo. The crude product was purified by flashchromatography (Isolute, 0-60% EtOAc in heptane) to give the titleintermediate: ¹H NMR (250 MHz, CDCl₃) delta 2.63 (3H, s), 4.80 (2H, s),6.60 (1H, s); LC-MS: m/z=+141.90 (M+H)+.

Step 2—Synthesis of 1-{5-[(oxan-2-yloxy)methyl]-1,2-oxazol-3-yl}ethanone

A solution of 1-[5-(hydroxymethyl)-1,2-oxazol-3-yl]ethanone (252 mg,1.79 mmol), 3,4-dihydro-2H-pyran (0.24 ml, 2.68 mmol) and pyridinium4-methylbenzenesulfonate (44.69 mg, 0.18 mmol) in DCM (10 mL) wasstirred at RT for 16 hr and then for a further 0.5 hr at 40° C. afterthe addition of more 3,4-dihydro-2H-pyran (0.24 ml, 2.68 mmol) andpyridinium 4-methylbenzenesulfonate (44.69 mg, 0.18 mmol). The reactionmixture was diluted with water (5 ml) and the solution extracted withDCM (2×20 ml). The combined organic layers were washed with brine (5ml), dried (Na₂SO₄), filtered and evaporated in vacuo. The crude productwas purified by flash chromatography (Isolute, 9:1 heptane:EtOAc) togive the title intermediate: ¹H NMR (500 MHz, CDCl₃) delta 1.56-1.53(2H, m), 1.68-1.60 (2H, m), 1.89-1.69 (2H, m), 2.65 (3H, s), 3.62-3.51(1H, m), 3.93-3.78 (1H, m), 4.68 (1H, d, J=13.9 Hz), 4.75 (1H, t, J=3.3Hz), 4.86-4.80 (1H, m), 6.63 (1H, s).

Step 3—Synthesis of2-{5-[(oxan-2-yloxy)methyl]-1,2-oxazol-3-yl}but-3-yn-2-ol

To a solution of ethynylmagnesium bromide (2.93 mL of a0.5M solution inTHF, 1.47 mmol) at 0° C. was slowly added1-{5-[(oxan-2-yloxy)methyl]-1,2-oxazol-3-yl}ethanone (220 mg, 0.98 mmol)in THF (5 mL). The reaction mixture was allowed to warm to RT andstirred for 45 minutes. The reaction mixture was quenched with aqueoussaturated NH₄Cl solution (10 mL) and the organics were removed in vacuo.The product was extracted into EtOAc (20 ml X²) and the combinedorganics were dried (Na₂SO₄), filtered and concentrated in vacuo. Thecrude product was purified by flash chromatography (Isolute column,10-30% EtOAc in heptanes) to give the title product as a pale yellowoil: ¹H NMR (250 MHz, CDCl₃) delta 1.93-1.40 (9H, m), 2.66 (1H, s), 2.85(1H, s), 3.69-3.46 (1H, m), 3.93-3.79 (1H, m), 4.94-4.54 (3H, m), 6.38(1H, s); LC-MS: m/z=+251.95 (M+H)+.

Step 4—Synthesis of1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-{5-[(oxan-2-yloxy)methyl]-1,2-oxazol-3-yl}but-1-yn-1-yl)-N,N-dimethylindazole-3-carboxamide

The title compound was prepared by procedure described in Example 61step 3, by substituting 2-(1,3-thiazol-2-yl)but-3-yn-2-ol with2-{5-[(oxan-2-yloxy)methyl]-1,2-oxazol-3-yl}but-3-yn-2-ol

in Step 3. The title compound was isolated as brown solid: LC-MS:m/z=+532.10 (M+H)+. This compound of 79% purity LC-MS (UV) was usedwithout further purification.

Step 5—Synthesis of1-(2-aminopyrimidin-4-yl)-6-{3-hydroxy-3-[5-(hydroxymethyl)-1,2-oxazol-3-yl]but-1-yn-1-yl}-N,N-dimethyl-1H-indazole-3-carboxamide

A solution of1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-{5-[(oxan-2-yloxy)methyl]-1,2-oxazol-3-yl}but-1-yn-1-yl)-N,N-dimethylindazole-3-carboxamide(110 mg, 0.21 mmol) and pyridinium 4-methylbenzenesulfonate (5.18 mg,0.2 mmol) in methanol (3 mL) was stirred at 60° C. for 1 hr, and then atRT for 3 days. Additional pyridinium 4-methylbenzenesulfonate was thenadded (20 mg, 0.8 mmol) and the reaction stirred at 55° C. for 1 hr. Thereaction mixture was concentrated in vacuo and then saturated aqueousNaHCO₃ (3 ml) solution was added. The product was extracted into DCM (5ml×2). The combined organics were washed with brine and dried (Na₂SO₄),filtered and concentrated in vacuo. The crude product was purified byflash chromatography (Isolute column) Elution with 3% methanol in DCMgave the title compound: 1H NMR (500 MHz, DMSO) delta 1.88 (3H, s), 3.12(3H, s), 4.57 (2H, d, J 6.0), 5.67 (1H, t, J 6.1), 6.55 (1H, s), 6.66(1H, s), 7.10 (1H, d, J 5.5), 7.16 (2H, s), 7.43 (1H, d, J 8.4), 8.01(1H, d, J 8.5), 8.35 (1H, d, J 5.5), 8.95 (1H, s); LC-MS m/z=+448.05(M+H)+.

Example 80 Preparation of1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]-N,N-dimethyl-1H-indazole-3-carboxamide

Step 1—Synthesis of1-(2-aminopyrimidin-4-yl)-N,N-dimethyl-6-[2(trimethylsily)ethynyl]indazole-3-carboxamide

To a mixture of1-(2-aminopyrimidin-4-yl)-6-bromo-N,N-dimethylindazole-3-carboxamide(61-b) (500 mg, 1.27 mmol), tetrakis(triphenylphosphine)palladium (118mg, 0.102 mmol), copper(I) iodide (19.4 mg, 0.102 mmol) andethynyl(trimethyl)silane 0.39 ml, 2.54 mmol) was added piperidine (3.1mL). The mixture was purged with nitrogen for 2 minutes and then stirredat 65° C. for 4 hr. The reaction mixture was concentrated in vacuo, DCM(5 mL) was added and the concentration repeated (×2). The crude productwas purified by flash chromatography (Biotage, 2-8% methanol in DCM) togive the title intermediate (250 mg): LC-MS: m/z=+379.45 (M+H)+.

Step 2—Synthesis of1-(2-aminopyrimidin-4-yl)-6-ethynyl-N,N-dimethylindazole-3-carboxamide

To a solution of1-(2-aminopyrimidin-4-yl)-N,N-dimethyl-6-[2-(trimethylsilyl)ethynyl]indazole-3-carboxamide(250 mg, 0.66 mmol) in methanol (5 mL) and DCM (10 mL) was added K₂CO₃(182.57 mg, 1.32 mmol). The reaction mixture was stirred for 1 hr andthen filtered by suction filtration. The precipitate was washed with DCMand methanol and the filtrate was concentrated in vacuo to give thetitle intermediate: ¹H NMR (250 MHz, DMSO) delta 3.08 (3H, s), 3.29 (3H,br. s.), 4.42 (1H, s), 7.06 (1H, d, J=5.63 Hz), 7.14 (2H, br. s.),7.41-7.48 (1H, m), 7.97 (1H, d, J=8.22 Hz), 8.31 (1H, d, J=5.48 Hz),9.04 (1H, s); LC-MS: m/z=+307.00 (M+H)+.

Step 3—Synthesis of1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]-N,N-dimethyl-1H-indazole-3-carboxamide

To a solution of1-(2-aminopyrimidin-4-yl)-6-ethynyl-N,N-dimethylindazole-3-carboxamide(80 mg, 0.217 mmol) in THF (1.0 mL) at −78° C. under nitrogen was added2M LDA in THF (0.27 mL, 0.54 mmol). After 5 minutes1-pyrimidin-2-yl-ethanone (79 mg, 0.65 mmol) in THF (0.5 mL) was addedand the reaction was allowed to warm to RT after 20 minutes. After afurther 30 minutes the reaction mixture was quenched by addition ofsaturated aqueous NH₄Cl (0.5 mL). The volatiles were removed in vacuoand the mixture was diluted with DCM (10 ml) and washed with water (2mL), dried (Na₂SO₄), filtered and concentrated in vacuo. The crudeproduct was purified by flash chromatography (Biotage, 0-2% methanol inDCM). Trituration of the partially purified product from EtOAc-heptanegave the title compound: ¹H NMR (250 MHz, MeOD) delta 1.93-2.02 (3H, m),3.22 (3H, s), 3.41 (3H, s), 7.24 (1H, d, J=5.79 Hz), 7.40-7.55 (2H, m),7.97 (1H, d, J=8.38 Hz), 8.29 (1H, d, J=5.79 Hz), 8.88 (2H, d, J=5.03Hz), 9.12 (1H, s); LC-MS: m/z=+429.45 (M+H)+.

Example 81 Preparation of1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(1H-pyrazol-1-ylmethyl)but-1-yn-1-yl]-N,N-dimethyl-1H-indazole-3-carboxamide

The title compound was prepared by procedure described for Example 80-cby substituting 1-pyrimidin-2-yl-ethanone with1-pyrazol-1-yl-propan-2-one in Step 3: ¹H NMR (500 MHz, MeOD) delta 1.54(3H, s), 3.22 (3H, s), 3.40 (3H, s), 4.45 (2H, s), 6.35 (1H, t, J=2.13Hz), 7.30 (1H, d, J=5.99 Hz), 7.41 (1H, dd, J=8.43, 1.18 Hz), 7.53 (1H,d, J=1.58 Hz), 7.80 (1H, d, J=2.05 Hz), 7.97 (1H, d, J=8.35 Hz), 8.29(1H, d, J=5.99 Hz), 9.01 (1H, s); LC-MS: m/z=+431.05 (M+H)+.

Example 82 Preparation of4-[1-(2-aminopyrimidin-4-yl)-3-[(morpholin-4-yl)carbonyl]-1H-indazol-6-yl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)but-3-yn-2-ol

Step 1—Synthesis of2-(5-methyl-1,3,4-oxadiazol-2-yl)-4-(trimethylsilyl)but-3-yn-2-ol

To a solution of isopropylmagnesium chloride lithium chloride complex(1.56 mL of a 1.3M solution in THF, 2.02 mmol) in dry THF (5 mL) at −15°C. under an atmosphere of nitrogen was introduced2-bromo-5-methyl-1,3,4-oxadiazole (300 mg, 1.84 mmol). The reactionmixture was warmed to −10° C. for 30 minutes. A solution of4-(trimethylsilyl)but-3-yn-2-one (0.37 ml, 2.21 mmol) in dry THF (5 mL)was added and the reaction mixture warmed to 0° C. for 1 hr. Afterfurther warming to RT for 30 minutes, the solution was cooled to 0° C.and saturated aqueous ammonium chloride (5 mL) introduced. The reactionmixture was extracted with DCM (3×10 mL extractions) and the combinedorganic extracts were dried (Na₂SO₄), filtered and concentrated invacuo. Purification of the residue by flash chromatography (Biotage,heptane/EtOAc followed by an EtOAc/MeOH gradient) furnished the titlecompound as an orange oil: ¹H NMR (500 MHz, CDCl₃) delta 0.18 (9H, s),1.95 (3H, s), 2.57 (3H, s), 3.13 (1H, s); LC-MS: m/z=+224.95 (M+H)+.

Step 2—Synthesis of4-{6-iodo-3-[(morpholin-4-yl)carbonyl]-1H-indazol-1-yl}pyrimidin-2-amine

To a solution of1-(2-aminopyrimidin-4-yl)-6-iodo-1H-indazole-3-carboxylic acid (3.00 g,7.87 mmol) in dry DCM (40 mL) was introduced thionyl chloride (6.85 mL,94.46 mmol) and DMF (3 drops, cat.). The reaction mixture was warmed to50° C. for 1 hr. After cooling to RT, the reaction mixture wasconcentrated in vacuo. The residue was re-dissolved in dry DCM (20 mL)and concentrated in vacuo (twice). After suspending the residue in dryDCM (30 mL), the solution was cooled to 0° C. under an atmosphere ofnitrogen, and morpholine (1.37 mL, 15.74 mmol) added dropwise. Thereaction mixture was warmed to RT for 16 hr. Following dilution with DCM(25 mL), 2M aqueous sodium carbonate (35 mL) was introduced. Theresulting precipitate was collected by filtration and washed on thefilter with DCM (5 mL) and dried. After suspension of the precipitate in3:1 water/acetonitrile (10 mL), the slurry was collected by filtrationand washed on the filter with further 3:1 water/acetonitrile (2×1 mLwashes). The filter cake was dried under vacuum to furnish the titlecompound as an off-white solid: ¹H NMR (500 MHz, DMSO) delta 3.41-3.76(6H, m), 3.85-3.97 (2H, m), 7.05 (1H, d, J=5.5 Hz), 7.18 (2H, s), 7.74(1H, dd, J=8.4, 1.1 Hz), 7.80 (1H, d, J=8.4 Hz), 8.34 (1H, d, J=5.5 Hz),9.33 (1H, s); LC-MS: m/z=+450.90 (M+H)+.

Step 3—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-3-[(morpholin-4-yl)carbonyl]-1H-indazol-6-yl]-2-(5-methyl-1,3,4-oxadiazol-2-yl)but-3-yn-2-ol

To a solution of4-{6-iodo-3-[(morpholin-4-yl)carbonyl]-1H-indazol-1-yl}pyrimidin-2-amine(95 mg, 0.19 mmol) in dry THF (3 mL) under an atmosphere of nitrogen wasintroduced bis(triphenylphosphine)palladium(II) chloride (13.3 mg, 0.02mmol), TBAF (0.23 mL of a 1M solution in THF, 0.23 mmol) and2-(5-methyl-1,3,4-oxadiazol-2-yl)-4-(trimethylsilyl)but-3-yn-2-ol. Thereaction mixture was warmed to 50° C. for 1.5 hr. After cooling to RT,the reaction mixture was diluted with saturated aqueous sodiumbicarbonate solution (4 ml) and extracted with EtOAc (2×10 mLextractions). The combined extracts were washed with water (5×5 mL),brine (5 mL), dried (Na₂SO₄) and filtered. After concentration of thefiltrate in vacuo, the residue was purified by flash chromatography(Biotage, DCM containing a 2-12% methanol gradient) to furnish the titlecompound as a pale brown solid: ¹H NMR (500 MHz, DMSO) delta 1.98 (3H,s), 2.56 (3H, s), 3.61-3.78 (6H, m), 3.90-3.97 (2H, m), 7.08 (1H, d,J=5.5 Hz), 7.10 (1H, s), 7.17 (2H, s), 7.48 (1H, dd, J=8.4, 1.1 Hz),8.05 (1H, d, J=8.4 Hz), 8.36 (1H, d, J=5.5 Hz), 9.00 (1H, s); LC-MS:m/z=+475.10 (M+H)+.

Example 83 Preparation of(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(2-hydroxypropan-2-yl)-1H-indazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

Step 1—Synthesis of methyl 6-bromo-1H-indazole-3-carboxylate

To a solution of 6-bromo-1H-indazole-3-carboxylic acid (1.5 g, 6.22mmol) in methanol (25 mL) was added thionyl chloride (2.26 ml, 31.12mmol). The mixture was heated at 60° C. for 1 hr. The reaction mixturewas cooled and concentrated in vacuo. The crude residue was dissolved inEtOAc (30 mL) and washed with saturated aqueous NaHCO₃ (10 mL), water(10 mL) and dried (Na₂SO₄), filtered and concentrated in vacuo to givethe title intermediate: ¹H NMR (500 MHz, CDCl₃) delta 4.08 (3H, s), 7.44(1H, d, J=8.6 Hz), 7.89 (1H, s), 8.09 (1H, d, J=8.7 Hz), 11.70 (1H, s);LC-MS: m/z=+254.85/256.75 (M+H)+.

Step 2—Synthesis of 2-(6-bromo-1H-indazol-3-yl)propan-2-ol

To a suspension of methyl 6-bromo-1H-indazole-3-carboxylate (500 mg,1.96 mmol) at 0° C. in THF (15 mL) was added methylmagnesium bromide (1Min THF, 15.29 ml, 15.29 mmol) dropwise. The reaction mixture was stirredat RT for 15 hr. Saturated aqueous NH₄Cl solution (75 mL) was added andthe product extracted into EtOAc (2×50 ml). The combined organics werewashed with water (20 mL) and dried (Na₂SO₄), filtered and concentratedin vacuo. The crude product was purified by flash chromatography(Biotage, 20-100% EtOAc in heptanes) gave the title intermediate as ayellow solid: ¹H NMR (500 MHz, CDCl₃) delta 1.75 (6H, s), 2.70 (1H, s),7.28 (1H, d, J=1.5 Hz), 7.63 (1H, d, J=1.0 Hz), 7.83 (1H, d, J=8.6 Hz),9.82 (1H, s); LC-MS: m/z=+254.85/256.90 (M+H)+.

Step 3—Synthesis of2-[1-(2-aminopyrimidin-4-yl)-6-bromoindazol-3-yl]propan-2-ol

To a solution of 2-(6-bromo-1H-indazol-3-yl)propan-2-ol (317 mg, 1.24mmol) in DMF (10 mL) was added NaH (60% oil dispersion, 79.5 mg, 1.99mmol) at 0° C. The reaction mixture was stirred at RT for 20 minutesbefore addition of 4-chloropyrimidin-2-amine (321.95 mg, 2.49 mmol). Themixture was stirred at RT for 10 minutes and then at 65° C. for 23 hr.The reaction mixture was quenched by addition of water (10 mL) and EtOAc(2 mL) was added. The resultant precipitate was collected by suctionfiltration and then thoroughly dried under high vacuum and trituratedfrom diethyl ether. The crude product was purified by flashchromatography (Biotage, 1-5% methanol in DCM) to give the titleintermediate as a pale yellow solid: ¹H NMR (500 MHz, DMSO) delta 1.63(6H, s), 5.59 (1H, s), 7.23-6.93 (3H, m), 7.49 (1H, dd, J=8.6, 1.5 Hz),8.07 (1H, d, J=8.6 Hz), 8.27 (1H, d, J=5.5 Hz), 9.11 (1H, d, J=1.4 Hz);LC-MS m/z=+347.95/349.80 (M+H)+.

Step 4—Synthesis of(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(2-hydroxypropan-2-yl)-1H-indazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

To a pressure tube was added2-[1-(2-aminopyrimidin-4-yl)-6-bromoindazol-3-yl]propan-2-ol followed bypiperidine (2.5 mL), tetrakis(triphenylphosphine)palladium (102.88 mg,0.09 mmol), copper(I) iodide (16.96 mg, 0.09 mmol) and(2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (269.16 mg, 1.78 mmol).The reaction was capped and stirred at 65° C. for 1.5 hr and thenconcentrated in vacuo. DCM (5 mL) was added to the reaction mixture andthe concentration was repeated (×2). The crude product was purified byflash chromatography (Biotage, 1-10% methanol in DCM) gave the titlecompound: ¹H NMR (500 MHz, DMSO) delta 1.63 (6H, s), 1.85 (3H, s), 2.41(3H, s), 5.57 (1H, s), 6.41 (1H, s), 6.56 (1H, s), 7.00 (2H, s), 7.05(1H, d, J=5.5 Hz), 7.33 (1H, dd, J=8.3, 1.2 Hz), 8.13 (1H, d, J=8.3 Hz),8.27 (1H, d, J=5.2 Hz), 8.88 (1H, s); LC-MS: m/z=+419.10 (M+H)+.

Example 84 Preparation of(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(2-hydroxypropan-2-yl)-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

The title compound was prepared by the procedure described in Example83-d; ¹H NMR (500 MHz, DMSO) delta 1.64 (6H, s), 1.90 (3H, s), 2.63 (3H,s), 5.58 (1H, s), 6.78 (1H, s), 7.01 (2H, s), 7.05 (1H, d, J=5.5 Hz),7.34 (1H, d, J=8.3 Hz), 8.27 (1H, d, J=5.5 Hz), 8.90 (1H, s); LC-MS:m/z=+420.

Example 85

The examples in Table 10 were prepared by procedure described in Example83-d by reacting 2-(6-bromo-1H-indazol-3-yl)propan-2-ol with theappropriate but-3-yn-2-ol intermediates.

TABLE 10 MS No. Structure Name 1H NMR (M + H) T10-85.1

4-[1-(2-aminopyrimidin-4-yl)- 3-(2-hydroxypropan-2-yl)-1H-indazol-6-yl]-2-(pyrimidin-2- yl)but-3-yn-2-ol (500 MHz, DMSO) delta8.91 (d, J = 4.89 Hz, 2H) 8.85 (s, 1H) 8.27 (d, J = 5.52 Hz, 1H) 8.11(d, J = 8.35 Hz, 1H) 7.52 (t, J = 4.81 Hz, 1H) 7.29 (d, J = 8.35 Hz, 1H)7.06 (d, J = 5.52 Hz, 1H) 7.00 (br. s., 2H) 6.24 (s, 1H) 5.57 (s, 1H)1.93 (s, 3H) 1.64 (s, 6H) 416.05 T10-85.2

7-{2-[1-(2-aminopyrimidin-4- yl)-3-(2-hydroxypropan-2-yl)-1H-indazol-6-yl]ethynyl}- 5H,6H,7H-cyclopenta [b]pyridin-7-ol (500MHz, DMSO) delta 1.63 (6H, s), 2.36-2.46 (1H, m), 2.60-2.70 (1H, m),2.96 (1H, dd, J = 8.12, 4.81 Hz), 3.02 (1H, t, J = 7.41 Hz), 5.56 (1H,s), 6.25 (1H, s), 6.98 (2H, br. s.), 7.05 (1H, d, J = 5.52 Hz),7.26-7.37 (2H, m), 7.75 (1H, d, J = 7.57 Hz), 8.12 (1H, d, J = 8.35 Hz),8.27 (1H, d, J = 5.52 Hz), 8.46 (1H, d, J = 4.26 Hz), 8.86 (1H, s)427.15

Example 86 Preparation of4-[1-(2-aminopyrimidin-4-yl)-3-(2-hydroxypropan-2-yl)-1H-indazol-6-yl]-2-(pyridin-2-yl)but-3-yn-2-ol

Step 1—Synthesis of methyl 6-iodo-1H-indazole-3-carboxylate

Preparation as described for methyl 6-bromo-1H-indazole-3-carboxylate:¹H NMR (500 MHz, MeOD) delta 4.03 (3H, s), 7.56 (1H, d, J=8.51 Hz), 7.91(1H, d, J=8.51 Hz), 8.06 (1H, s); LC-MS: m/z=+302.85 (M+H)+.

Step 2—Synthesis of 2-(6-iodo-1H-indazol-3-yl)propan-2-ol

Preparation as described for 2-(6-bromo-1H-indazol-3-yl)propan-2-ol: ¹HNMR (500 MHz, CDCl₃) delta 1.75 (6H, s), 2.69 (1H, s), 7.45 (1H, dd,J=8.51, 1.42 Hz), 7.72 (1H, d, J=8.51 Hz), 7.87 (1H, s), 9.74 (1H, br.s.); LC-MS: m/z=+302.85 (M+H)+.

Step 3—Synthesis of2-[1-(2-aminopyrimidin-4-yl)-6-iodo-1H-indazol-3-yl]propan-2-ol

To a solution of 2-(6-iodo-1H-indazol-3-yl)propan-2-ol (1.00 g, 3.31mmol) in dry DMF (30 mL) at 0° C. under an atmosphere of nitrogen wasintroduced sodium hydride (212 mg of a 60% dispersion in mineral oil,5.3 mmol). After 20 minutes at this temperature,4-chloropyrimidin-2-amine (858 mg, 6.62 mmol) was added and the solutionwarmed to RT for 10 minutes, then to 65° C. for 23 hr. The reactionmixture was cooled to RT, quenched carefully with water (20 mL) andextracted with EtOAc (2×20 mL extractions). The organic extracts werecombined, dried (MgSO₄), filtered and concentrated in vacuo.Purification of the residue by silica gel flash column chromatography(4:1 to 1:1 heptane/EtOAc gradient) furnished the title compound as anoff-white solid: ¹H NMR (250 MHz, CDCl₃) delta 1.73-1.83 (6H, m), 2.77(1H, s), 5.16 (2H, s), 7.23-7.33 (1H, m), 7.55-7.64 (1H, m), 7.68-7.78(1H, m), 8.30 (1H, d, J=5.79 Hz), 9.15-9.28 (1H, m); LC-MS: m/z=+395.90(M+H)+.

Step 4—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-3-(2-hydroxypropan-2-yl)-1H-indazol-6-yl]-2-(pyridin-2-yl)but-3-yn-2-ol

To a solution of2-[1-(2-aminopyrimidin-4-yl)-6-iodo-1H-indazol-3-yl]propan-2-ol (150 mg,0.36 mmol) in piperidine (2 mL) was introducedtetrakis(triphenylphosphine)palladium (0) (16.8 mg, 0.02 mmol),copper(I) iodide (2.8 mg, 0.02 mmol) and 2-(pyridin-2-yl)but-3-yn-2-ol(112 mg, 0.73 mmol). The reaction was warmed to 35° C. for 1 hr. Aftercooling to RT, the reaction mixture was concentrated in vacuo and theresidue purified by flash chromatography (Biotage, DCM containing a1-10% MeOH gradient) to furnish the title compound as a brown oil: ¹HNMR (500 MHz, CDCl₃) delta 1.78 (6H, s), 1.94 (3H, s), 2.84 (1H, br.s.), 5.18 (2H, br. s.), 5.80 (1H, br. s.), 7.19-7.39 (1H, m), 7.74 (1H,d, J=7.88 Hz), 7.82 (1H, td, J=7.72, 1.58 Hz), 7.90 (1H, d, J=8.35 Hz),8.29 (1H, d, J=5.36 Hz), 8.58 (1H, d, J=4.73 Hz), 8.89 (1H, s); LCMS:m/z=+415.05 (M+H)+.

Example 87 Preparation of4-[1-(2-aminopyrimidin-4-yl)-3-(2-hydroxypropan-2-yl)-1H-indazol-6-yl]-2-(1-methyl-1H-pyrazol-3-yl)but-3-yn-2-ol

Step 1—Synthesis of2-(1-methyl-1H-pyrazol-3-yl)-4-(trimethylsilyl)but-3-yn-2-ol

To a solution of 3-iodo-1-methyl-1H-pyrazole (378 mg, 1.82 mmol) in dryDCM (15 mL) at 0° C. under an atmosphere of nitrogen, was introducedethylmagnesium bromide (2.0 mL of a 1.0M solution in THF, 2.0 mmol).After 30 minutes at 0° C., the reaction mixture was warmed to RT for 15minutes, then introduced to a solution of4-(trimethylsilyl)but-3-yn-2-one (0.37 ml, 2.18 mmol) in dry DCM (5 ml)at 0° C. under an atmosphere of nitrogen. The reaction mixture waswarmed to RT for 16 hr. Following addition of saturated aqueous ammoniumchloride (5 ml), the reaction mixture was extracted with DCM (3×5 mLextractions). The combined organic extracts were dried (Na₂SO₄),filtered and concentrated in vacuo. Purification of the residue bysilica gel flash column chromatography (heptane/EtOAc gradient)furnished the title compound as an orange-brown oil: ¹H NMR (500 MHz,CDCl₃) delta 0.15 (9H, d, J=3.5 Hz), 1.82 (3H, s), 3.18 (1H, s), 3.86(3H, s), 6.28 (1H, d, J=2.2 Hz), 7.26 (1H, d, J=2.2 Hz); LC-MS:m/z=+222.95 (M+H)+.

Step 2-Synthesis of4-[1-(2-aminopyrimidin-4-yl)-3-(2-hydroxypropan-2-yl)-1H-indazol-6-yl]-2-(1-methyl-1H-pyrazol-3-yl)but-3-yn-2-ol

To a solution of2-[1-(2-aminopyrimidin-4-yl)-6-iodo-1H-indazol-3-yl]propan-2-ol (135 mg,0.31 mmol) in dry THF (4 mL) under an atmosphere of nitrogen wasintroduced bis(triphenylphosphine)palladium(II) chloride (21.6 mg, 0.03mmol), TBAF (0.37 mL of a 1M solution in THF, 0.37 mmol) and2-(1-methyl-1H-pyrazol-3-yl)-4-(trimethylsilyl)but-3-yn-2-ol (137 mg,0.62 mmol). The reaction mixture was warmed to 50° C. for 1.5 hr. Aftercooling to RT, the reaction mixture was diluted with saturated aqueoussodium bicarbonate solution (4 ml) and extracted with EtOAc (2×10 mLextractions). The combined extracts were washed with water (5×5 mL),brine (5 mL), dried (Na₂SO₄) and filtered. After concentration of thefiltrate in vacuo, the residue was purified by silica gel flash columnchromatography (DCM containing a 1-10% methanol gradient) to furnish thetitle compound as an off-white solid: ¹H NMR (DMSO, 500 MHz) delta 1.63(6H, s), 1.83 (3H, s), 3.82 (3H, s), 5.57 (1H, s), 6.02 (1H, s), 6.36(1H, d, J=2.1 Hz), 6.99 (2H, s), 7.05 (1H, d, J=5.5 Hz), 7.31 (1H, d,J=8.4 Hz), 7.61 (1H, d, J=2.0 Hz), 8.11 (1H, d, J=8.3 Hz), 8.27 (1H, d,J=5.5 Hz), 8.84 (1H, s); LC-MS: m/z=+418.10 (M+H)+.

Example 88 Preparation of(R)-4-[1-(2-Amino-pyrimidin-4-yl)-3-hydroxymethyl-1H-indazol-6-yl]-2-(5-methyl-isoxazol-3-yl)-but-3-yn-2-ol

The title compound was prepared under the same conditions as describedfor Example 83-d using(2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol; ¹H NMR (250 MHz,DMSO) delta 1.85 (3H, s), 2.41 (3H, s), 4.84 (2H, d, J=5.94 Hz),5.47-5.66 (1H, m), 6.41 (1H, d, J=0.76 Hz), 6.57 (1H, s), 7.04 (3H, d,J=5.63 Hz), 7.36 (1H, dd, J=8.22, 1.22 Hz), 7.96 (1H, d, J=8.22 Hz),8.27 (1H, d, J=5.48 Hz), 8.88 (1H, s); LC-MS: m/z=+391.0 (M+H)+

Example 89 Preparation of(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(hydroxymethyl)-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

The title compound was prepared under the same conditions as describedfor Example 83-d using(2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol; ¹H NMR (500 MHz,MeOD) delta 1.98 (3H, s), 2.65 (3H, s), 4.97 (2H, s), 7.23 (1H, d,J=5.67 Hz), 7.40 (1H, dd, J=8.28, 1.18 Hz), 7.90 (1H, d, J=8.20 Hz),8.22 (1H, d, J=5.52 Hz), 9.03 (1H, s); LC-MS: m/z=+392.00 (M+H)+.

Example 90 Preparation of4-[1-(2-aminopyrimidin-4-yl)-3-(hydroxymethyl)-1H-indazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol

The title compound was prepared under the same conditions as describedfor Example 83-d using 2-(pyrimidin-2-yl)but-3-yn-2-ol; ¹H NMR (500 MHz,DMSO) delta 1.92 (3H, s), 4.79-4.88 (2H, m), 5.59 (1H, t, J=5.83 Hz),6.26 (1H, s), 7.00 (2H, br. s.), 7.05 (1H, d, J=5.52 Hz), 7.32 (1H, dd,J=8.28, 1.18 Hz), 7.50 (1H, t, J=4.89 Hz), 7.94 (1H, d, J=11.98 Hz),8.27 (1H, d, J=6.62 Hz), 8.82-8.86 (1H, m), 8.90 (2H, d, J=6.46 Hz);LC-MS: m/z=+388.05 (M+H)+.

Example 91 Preparation of(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(fluoromethyl)-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

Step 1—Synthesis of ethyl1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazole-3-carboxylate

To a solution of1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazole-3-carboxylic acid (2.00 g,5.62 mmol) in dry DCM (10 mL) was introduced thionyl chloride (8.2 mL,112.6 mmol) and DMF (0.1 mL, cat.). The solution was warmed to refluxfor 18 hr under an atmosphere of nitrogen. After cooling to roomtemperature, the precipitous solution was filtered and the filter cakewashed with DCM (5 mL). The washed precipitate was quickly introduced toethanol (25 mL) at RT with rapid stirring for 3 hr. Followingconcentration of the reaction mixture in vacuo, the residue wassuspended in sodium bicarbonate (20 mL of 1M aq NaHCO₃) and extractedwith EtOAc (3×50 mL extractions). The combined organic extracts werewashed with brine (20 mL), dried (Na₂SO₄), filtered and evaporated tofurnish the crude title compound as a pale brown solid: ¹H NMR (500 MHz,DMSO) delta 1.40 (3H, t, J=7.09 Hz), 4.46 (2H, q, J=7.09 Hz), 7.12 (1H,d, J=5.52 Hz), 7.24 (2H, br. s.), 7.66 (1H, dd, J=8.67, 1.58 Hz), 8.10(1H, d, J=8.67 Hz), 8.38 (1H, d, J=5.52 Hz), 9.21 (1H, d, J=1.26 Hz);LC-MS: m/z=+361.95/363.80 (M+H)+. This compound, with LC-MS purity=64%UV, was used in the next step without further purification.

Step 2—Synthesis of[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazol-3-yl]methanol

To a solution ethyl1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazole-3-carboxylate (500 mg,0.88 mmol) in dry THF (4 mL) at 0° C. under an atmosphere of nitrogenwas introduced lithium aluminium hydride (3.5 mL of a 1M solution inTHF, 3.50 mmol). After 10 minutes at this temperature, the reactionmixture was quenched by carefully transferring into a rapidly stirredsaturated aqueous solution of Rochelle's salt (5 mL). The suspension wasextracted with DCM (10 mL) and the organic extract filtered through apad of Celite®. The filtrate was washed with water (5 mL) and brine (5mL), dried (Na₂SO₄), filtered and the filtrate concentrated in vacuo tofurnish the crude title compound as a colorless solid: ¹H NMR (250 MHz,DMSO) delta 4.84 (2H, d, J=5.48 Hz), 5.61 (1H, t, J=5.71 Hz), 7.04 (3H,s), 7.51 (1H, dd, J=8.45, 1.75 Hz), 7.92 (1H, d, J=8.53 Hz), 8.28 (1H,d, J=5.48 Hz), 9.11 (1H, d, J=1.22 Hz); LC-MS: m/z=+319.90/321.80(M+H)+. This compound, with LC-MS purity=76% UV, was used in the nextstep without further purification.

Step 3—Synthesis of4-[6-bromo-3-(fluoromethyl)-1H-indazol-1-yl]pyrimidin-2-amine

To a solution of[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazol-3-yl]methanol (200 mg,0.47 mmol) in dry DCM (10 mL) at RT under an atmosphere of nitrogen wasintroduced (diethylamino)sulphur trifluoride (0.08 mL, 0.63 mmol). After16 hr at this temperature, the reaction mixture was treated with sodiumbicarbonate (25 mL of saturated aq NaHCO₃) and extracted with DCM (2×20mL extractions). The combined organic extracts were dried (Na₂SO₄),filtered and concentrated in vacuo. The residue was purified by columnchromatography (Biotage, heptane/EtOAc gradient) to furnish the titlecompound as a colorless solid: ¹H NMR (500 MHz, DMSO) delta 5.86 (2H, d,J=48.24 Hz), 7.06 (1H, d, J=5.04 Hz), 7.14 (2H, br. s.), 7.58 (1H, dd,J=8.04, 2.05 Hz), 7.92 (1H, d, J=8.98 Hz), 8.31 (1H, d, J=6.31 Hz), 9.17(1H, d, J=1.42 Hz); LC-MS: m/z=+321.90/323.90 (M+H)+.

Step 4—Synthesis of(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(fluoromethyl)-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

To a solution of4-[6-bromo-3-(fluoromethyl)-1H-indazol-1-yl]pyrimidin-2-amine (70 mg,0.21 mmol) in piperidine (2 mL) was introducedtetrakis(triphenylphosphine)palladium (0) (19 mg, 0.02 mmol), copper(I)iodide (3 mg, 0.02 mmol) and(2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (90 mg, 0.41 mmol).The reaction mixture was warmed to 66° C. for 2 hr, re-treated with(2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (45 mg, 0.20 mmol)and warming continued at 66° C. for a further 1 hr. Following cooling toRT, the reaction mixture was concentrated in vacuo, DCM (10 mL) wasadded and the solution re-evaporated to dryness in vacuo (re-evaporationprocess repeated twice). Purification of the residue by columnchromatography (Biotage, DCM containing a 0-10% gradient of methanol)furnished a brown oil which was suspended in acetonitrile andconcentrated in vacuo. The residue was slurried in diethyl ether (0.5mL) to which was introduced acetonitrile until a fine cream precipitateresulted. Filtration furnished the title compound as a cream solid: ¹HNMR (500 MHz, DMSO) delta 1.90 (3H, s), 2.62 (3H, s), 5.85 (2H, d,J=47.45 Hz), 6.82 (1H, s), 6.95-7.23 (3H, m), 7.43 (1H, dd, J=8.28, 1.18Hz), 7.98 (1H, d, J=8.20 Hz), 8.33 (1H, d, J=5.36 Hz), 8.94 (1H, s);LC-MS: m/z=+394.00 (M+H)+.

Example 92 Preparation of4-[1-(2-aminopyrimidin-4-yl)-3-(fluoromethyl)-1H-indazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol

To a solution of4-[6-bromo-3-(fluoromethyl)-1H-indazol-1-yl]pyrimidin-2-amine (49 mg,0.12 mmol) in piperidine (2 mL) was introducedtetrakis(triphenylphosphine)palladium (0) (11.5 mg, 0.01 mmol),copper(I) iodide (1.9 mg, 0.01 mmol) and 2-(pyrimidin-2-yl)but-3-yn-2-ol(39 mg, 0.25 mmol). The reaction mixture was warmed to 66° C. for 2 hr.After cooling to RT, the reaction mixture was concentrated in vacuo, DCM(10 mL) was added and the solution re-evaporated to dryness in vacuo(re-evaporation process repeated twice). Purification of the residue bycolumn chromatography (Biotage, DCM containing a 0-10% gradient ofmethanol) furnished a brown oil which was suspended in acetonitrile andconcentrated in vacuo. The residue was re-suspended in acetonitrile (1mL), whereupon a brown solid precipitated and was collected byfiltration to furnish the title compound as a brown solid: ¹H NMR (500MHz, METHANOL-d4) delta 1.99 (3H, s), 5.75 (2H, d, J=47.92 Hz), 7.23(1H, d, J=5.36 Hz), 7.42 (1H, dd, J=8.28, 1.02 Hz), 7.48 (1H, t, J=4.89Hz), 7.85 (1H, d, J=8.20 Hz), 8.25 (1H, d, J=4.73 Hz), 8.88 (2H, d,J=4.89 Hz), 9.06 (1H, s); LC-MS: m/z=+390.05 (M+H)+.

Example 93 Preparation of(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(2-fluoropropan-2-yl)-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

Step 1—Synthesis of4-[6-bromo-3-(2-fluoropropan-2-yl)-1H-indazol-1-yl]pyrimidin-2-amine

To a solution of2-[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazol-3-yl]propan-2-ol (200mg, 0.57 mmol) in dry DCM (2 mL) at 0° C. under an atmosphere ofnitrogen was introduced (diethylamino)sulphur trifluoride (0.14 mL, 1.15mmol). The reaction was left to warm to RT for 1 hr. Following additionof sodium bicarbonate (5 mL of a saturated aqueous solution), thereaction mixture was washed with DCM (2×5 mL), and the combined organicextracts dried (Na₂SO₄), filtered and concentrated in vacuo. The residuewas purified by flash chromatography (Biotage, eluent heptane:EtOAc[0-100%] gradient) to furnish the title compound as a yellow solid: ¹HNMR (500 MHz, CDCl₃) delta 1.81-1.97 (6H, m), 5.18 (2H, br. s.), 7.28(1H, s), 7.40-7.50 (1H, m), 7.78-7.92 (1H, m), 8.32 (1H, d, J=5.67 Hz),9.01 (1H, d, J=1.10 Hz); LC-MS: m/z=+349.95/351.80 (M+H)+.

Step 2 Synthesis of(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(2-fluoropropan-2-yl)-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

To a solution of4-[6-bromo-3-(2-fluoropropan-2-yl)-1H-indazol-1-yl]pyrimidin-2-amine (95mg, 0.26 mmol) in piperidine (1 mL) was introducedtetrakis(triphenylphosphine)palladium (0) (24 mg, 0.02 mmol), copper(I)iodide (4 mg, 0.02 mmol) and(2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (79 mg, 0.52 mmol).The reaction mixture was warmed to 66° C. for 2 hr. After cooling to RT,the reaction mixture was concentrated in vacuo and the residue purifiedby flash chromatography (Biotage, eluent:DCM containing a 1-10% MeOHgradient). Further purification by reverse phase preparative HPLCfurnished the title compound as an orange solid: ¹H NMR (500 MHz, DMSO)delta 1.76-2.00 (9H, m), 2.62 (3H, s), 6.82 (1H, s), 6.95-7.15 (3H, m),7.39 (1H, d, J=9.93 Hz), 7.95 (1H, d, J=9.93 Hz), 8.33 (1H, br. s.),8.94 (1H, s); LC-MS: m/z=+422.05 (M+H)+.

Example 94 Preparation of(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(3,3-difluoro-2-hydroxy-2-methylpropyl)-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

Step 1—Synthesis of3-[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazol-3-yl]-1,1-difluoro-2-methylpropan-2-ol

To a solution of 4-(6-bromo-3-methyl-1H-indazol-1-yl)pyrimidin-2-amine(500 mg, 1.64 mmol) in dry THF (5 mL) at −78° C. under an atmosphere ofnitrogen, was introduced lithium diisopropylamide (2.1 mL of a 2Msolution in THF, 4.11 mmol). After 5 minutes, a solution of1,1-difluoropropan-2-one (0.4 mL, 4.93 mmol) in dry THF (2 mL) wasadded. The reaction mixture was warmed to RT after 20 minutes at −78° C.After 30 minutes at RT, the reaction mixture was quenched (5 mL of sat.aq. ammonium chloride) and concentrated in vacuo. The residue wasdiluted with DCM (10 mL), washed with water (2 mL) and the organicextract dried (Na₂SO₄), filtered and concentrated in vacuo. Purificationof the residue by flash chromatography (Biotage, elution with DCMcontaining a 1-12% gradient of MeOH) furnished the title compound as ayellow solid: ¹H NMR (500 MHz, CDCl₃) delta 1.36 (3H, s), 3.19 (1H, d,J=15.1 Hz), 3.34 (1H, d, J=14.9 Hz), 3.40 (1H, s), 5.17 (2H, s), 5.67(1H, t, J=56.3 Hz), 7.24 (1H, d, J=8.5, 1.5 Hz), 7.45 (1H, dd, J=8.5,1.5 Hz), 7.61 (1H, d, J=8.5 Hz), 8.32 (1H, d, J=5.6 Hz), 9.00 (1H, d,J=1.4 Hz); LC-MS: m/z=+397.90/399.90 (M+H)+.

Step 2—Synthesis of(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(3,3-difluoro-2-hydroxy-2-methylpropyl)-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

To a solution of3-[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-indazol-3-yl]-1,1-difluoro-2-methylpropan-2-ol(75 mg, 0.19 mmol) in piperidine (1 mL) was introducedtetrakis(triphenylphosphine)palladium (0) (21.7 mg, 0.02 mmol),copper(I) iodide (3.6 mg, 0.02 mmol) and(2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (57 mg, 0.38 mmol).The reaction mixture was warmed to 65° C. for 1.5 hr under an atmosphereof nitrogen. After cooling to RT, the reaction mixture was re-treatedwith additional tetrakis(triphenylphosphine)palladium (0) (21.7 mg, 0.02mmol), copper(I) iodide (3.6 mg, 0.02 mmol) and(2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (57 mg, 0.38 mmol).The reaction mixture was warmed to 65° C. for a further 3 hr. Aftercooling to RT, the reaction mixture was concentrated in vacuo.Purification of the residue by flash chromatography (Biotage, eluent 9:1DCM/MeOH) furnished a partially purified product. Further purificationby reverse phase preparative HPLC gave the title compound as a brownsolid: ¹H NMR (500 MHz, DMSO) delta 1.17 (3H, s), 1.90 (3H, s), 2.63(3H, s), 3.09 (1H, d, J 14.2), 3.21 (1H, d, J 14.2), 5.50 (1H, s), 5.92(1H, t, J 56.1), 6.78 (1H, s), 7.01 (2H, s), 7.08 (1H, d, J 5.5), 7.36(1H, dd, J 8.3, 1.2), 7.94 (1H, d, J 8.3), 8.29 (1H, d, J 5.5), 8.89(1H, s); LC-MS: m/z=+470.05 (M+H)+.

Example 95 Preparation of(2R)-4-[1-(2-aminopyrimidin-4-yl)-5-fluoro-3-methyl-1H-indazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

Step 1—Synthesis of 1-(4-bromo-2,5-difluorophenyl)ethanone

To a stirred mixture of 2-bromo-1,4-difluorobenzene (3.24 g, 16.81 mmol)and aluminium chloride (5.82 g, 43.7 mmol) at 60° C. under nitrogen wasadded dropwise acetyl chloride (1.98 g, 25.28 mmol 1). The mixture wasstirred at 95° C. for 1.5 hr and then poured into ice (50 mL). To themixture was added HCl (3 mL) followed by extraction into ether (20mL×2). The ether extracts were washed with brine (20 mL) and thenconcentrated under reduced pressure to obtain the desired crude product(brown oil) as mixture with starting material (˜55:45) (2.67 g, 33%); 1HNMR (250 MHz, CHLOROFORM-d) delta 2.64 (3H, d, J=5.18 Hz), 7.42 (1H, dd,J=9.44, 5.18 Hz), 7.65 (1H, dd, J=8.45, 6.17 Hz).

Step 2—Synthesis of(E)-[1-(4-bromo-2,5-difluorophenyl)ethylidene]hydrazine

1-(4-bromo-2,5-difluorophenyl)ethanone (500 mg, 1.042 mmol) wasdissolved in ethanol (10 mL), then hydrazine hydrate (57.4 mg, 1.147mmol) added and stirred at RT for 16 hr. A pale yellow solid wasfiltered off and the filtrate was concentrated under reduced pressure toobtain the crude title compound as a brown-yellow solid (249 mg, 54%yield); 1H NMR (500 MHz, CHLOROFORM-d) delta 2.13 (3H, d, J=2.99 Hz),7.28 (1H, dd, J=9.85, 5.60 Hz), 7.34 (1H, dd, J=9.14, 6.62 Hz).

Step 3—Synthesis of 6-bromo-5-fluoro-3-methyl-1H-indazole

A solution of (E)-[1-(4-bromo-2,5-difluorophenyl)ethylidene]hydrazine inethylene glycol (3 mL) was heated at 165° C. for 3 hours in a sealedtube. The mixture was cooled to RT and saturated NaHCO₃ was added (3 mL)and stirred for 10 minutes. The mixture was filtered and solid waswashed with water (5 mL×2) to obtain the desired product brown solid(163 mg, 62%).

1H NMR (500 MHz, METHANOL-d4) delta 2.51-2.55 (3H, m), 7.52 (1H, d,J=9.30 Hz), 7.75 (1H, d, J=5.52 Hz), 7.72-7.78 (1H, m). LC-MS: m/z:+229, 231 (M+H)+.

Step 4—Synthesis of4-(6-bromo-5-fluoro-3-methylindazol-1-yl)pyrimidin-2-amine

To a solution of 6-bromo-5-fluoro-3-methyl-1H-indazole (130 mg, 0.284mmol, 50% purity) in DMF (2 ml) was added NaH (60% oil dispersion, 18.16mg, 0.454 mmol) at 0° C. The reaction mixture stirred for 15 minutesbefore the slow addition of a solution of 4-chloropyrimidin-2-amine(73.53 mg, 0.568 mmol) in DMF (2 mL). The resulting mixture was stirredat 60° C. for 16 hr. The reaction mixture was cooled and partitionedbetween water (15 ml) and EtOAc (15 ml). A precipitate formed and wascollected by suction filtration. The filtrate was concentrated in vacuoand purified by flash chromatography (Isolute column, 1-2% methanol inDCM) to give the title intermediate as a yellow oil: ¹H NMR (500 MHz,DMSO) delta 2.56 (3H, s), 7.00 (1H, s), 7.04-7.14 (2H, m), 7.92 (1H, d,J=8.35 Hz), 8.26 (1H, d, J=5.52 Hz), 9.22 (1H, d, J=5.99 Hz); LC-MS:m/z=+321.90, 323.80 (M+H)+.

Step 5—Synthesis of(2R)-4-[1-(2-aminopyrimidin-4-yl)-5-fluoro-3-methyl-1H-indazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

The title compound was prepared by the procedure described in Example2-b by reacting4-(6-bromo-5-fluoro-3-methylindazol-1-yl)pyrimidin-2-amine with(2R)-2-(1,3-thiazol-2-yl)but-3-yn-2-ol: ¹H NMR (500 MHz, DMSO) delta1.96 (3H, s), 2.55 (3H, s), 7.02 (3H, s), 7.15 (1H, br. s), 7.71 (1H, d,J=3.15 Hz), 7.79 (1H, s), 7.82 (1H, d, J=8.83 Hz), 8.26 (1H, d, J=5.52Hz), 8.92 (1H, d, J=6.46 Hz); LC-MS m/z=+395.35 (M+H)+.

Example 96 Preparation of4-[1-(2-amino-6-chloropyrimidin-4-yl)-3-[(morpholin-4-yl)carbonyl]-1H-indazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-olMono Formate Salt

Step 1 Synthesis of1-(2-amino-6-chloropyrimidin-4-yl)-6-iodo-1H-indazole-3-carboxylic Acid

To a solution of 6-iodo-1H-indazole-3-carboxylic acid (3.00 g, 10.42mmol) in dry DMF (50 mL) at 0° C. under an atmosphere of nitrogen wasintroduced sodium hydride (1.25 g of a 60% dispersion in mineral oil,31.25 mmol). The reaction mixture was warmed to RT for 15 mins4,6-Dichloropyrimidin-2-amine (2.56 g, 15.62 mmol) was then added, andthe solution warmed to 60° C. for 18 hr. After cooling to 0° C., thereaction was carefully quenched with water (50 mL) and acidified byaddition of 0.5M aqueous citric acid. The resulting precipitate wascollected by filtration, washed on the filter with 1:1 methanol/EtOAcand dried under vacuum to furnish the title compound as a beige solid:LC-MS: m/z=+415.85/417.90 (M+H)+. This compound, with LC-MS purity=70%UV, was used in the next step without further purification.

Step 2 Synthesis of1-(2-amino-6-chloropyrimidin-4-yl)-6-[3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]-1H-indazole-3-carboxylicAcid

To a solution of1-(2-amino-6-chloropyrimidin-4-yl)-6-iodo-1H-indazole-3-carboxylic acid(750 mg, 1.81 mmol) in 1:1 triethylamine/dry THF (12 mL) was introducedbis(triphenylphosphine)palladium(II) chloride (127 mg, 0.18 mmol),copper(I) iodide (34 mg, 0.18 mmol) and 2-(pyrimidin-2-yl)but-3-yn-2-ol(535 mg, 3.61 mmol). The reaction mixture was warmed to 55° C. for 1 hr.After cooling to RT, the reaction mixture was concentrated in vacuo tofurnish the crude title compound: ¹H NMR (500 MHz, DMSO) delta 1.92 (3H,s), 6.26 (1H, s), 7.09 (1H, s), 7.39 (1H, d, J=8.2 Hz), 7.51 (1H, t,J=4.9 Hz), 8.23 (1H, d, J=8.6 Hz), 8.82 (1H, s), 8.90 (2H, d, J=4.9 Hz);LC-MS: m/z=+436.05/437.70 (M+H)+. This compound, with LC-MS purity=91%UV, was used in the next step without further purification.

Step 3 Synthesis of4-[1-(2-amino-6-chloropyrimidin-4-yl)-3-[(morpholin-4-yl)carbonyl]-1H-indazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-olMono Formate Salt

To a solution of1-(2-amino-6-chloropyrimidin-4-yl)-6-[3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]-1H-indazole-3-carboxylicacid (250 mg, 0.51 mmol) in DMF (5 mL) was introducedO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (262 mg, 0.69 mmol), morpholine (60 mg, 0.69 mmol)and triethylamine (0.1 mL, 0.69 mmol). After 3 hr at RT, the reactionmixture was diluted with water (2 ml) and extracted with EtOAc (2×5 mLextractions). The combined organic extracts were washed with water (5mL) and brine (5 ml), dried (Na₂SO₄), filtered and concentrated invacuo. Purification of the residue by reverse phase preparative HPLCfurnished the title compound as a beige solid: ¹H NMR (500 MHz, DMSO)delta 1.92 (3H, s), 3.59-3.77 (6H, m), 3.86-3.92 (2H, m), 6.27 (1H, s),7.06 (1H, s), 7.40 (1H, dd, J=8.4, 1.1 Hz), 7.51 (1H, t, J=4.9 Hz), 7.67(2H, s), 7.98 (1H, d, J=8.3 Hz), 8.85 (1H, s), 8.90 (2H, d, J=4.9 Hz);LC-MS: m/z=+505.15/507.20 (M+H)+.

Example 97 Preparation of1-[2-amino-6-(methylamino)pyrimidin-4-yl]-6-[3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]-N,N-dimethyl-1H-indazole-3-carboxamide

Step 1—Synthesis of1-[2-amino-6-(methylamino)pyrimidin-4-yl]-6-iodo-N,N-dimethyl-1H-indazole-3-carboxamide

To a suspension of 6-iodo-N,N-dimethyl-1H-indazole-3-carboxamide (100mg, 0.32 mmol) at 0° C. in DMF (3 mL) was added sodium hydride (19 mg ofa 60% dispersion in mineral oil, 0.47 mmol). The reaction mixture wasallowed to warm to RT over 15 minutes before the addition of6-chloro-4-N-methylpyrimidine-2,4-diamine (75 mg, 0.47 mmol). Thereaction mixture was then heated at 180° C. for 2 hr. The reactionmixture was allowed to cool to RT. The mixture was cooled to 0° C. andquenched by addition of water (1 mL) and the volatiles evaporated invacuo. The mixture was diluted with sat ammonium chloride (20 mL) andextracted with ethyl acetate (3×50 mL). The combined organic extractswere dried (Na₂SO₄), filtered and evaporated in vacuo. Purification ofthe residue by column chromatography (Biotage, 55-100% ethyl acetate:heptanes) gave the title compound: ¹H NMR (500 MHz, DMSO) delta 2.78(3H, s), 3.08 (3H, s), 3.42 (3H, s), 6.24 (1H, s), 6.48 (2H, s), 7.08(1H, s), 7.64 (1H, m), 7.79 (1H, m), 9.40 (1H, s); LC-MS: m/z=+438.0(M+H)+.

Step 2—Synthesis of1-[2-amino-6-(methylamino)pyrimidin-4-yl]-6-[3-hydroxy-3-(pyrimidin-2-yl)but-1-yn-1-yl]-N,N-dimethyl-1H-indazole-3-carboxamide

To a sealed tube was added1-[2-amino-6-(methylamino)pyrimidin-4-yl]-6-iodo-N,N-dimethyl-1H-indazole-3-carboxamide(86 mg, 0.20 mmol), followed by piperidine (2 mL),tetrakis(triphenylphosphine)palladium (23 mg, 0.02 mmol), copper(I)iodide (4 mg, 0.02 mmol) and 2-(pyrimidin-2-yl)but-3-yn-2-ol (58 mg,0.39 mmol). The reaction mixture was purged with nitrogen gas, cappedand stirred at room temperature for 1.5 hr. After cooling to RT, thereaction mixture was concentrated in vacuo. EtOAc (5 mL) was added andconcentration in vacuo repeated. The residue was purified using columnchromatography (Biotage, 0-10% gradient of methanol in DCM) to give abrown solid. Trituration of the solid with ethyl acetate/heptane gavethe title compound. ¹H NMR (DMSO, 500 MHz) delta 1.92 (3H, s), 2.80 (3H,d, J=4.1 Hz), 3.10 (3H, s), 3.31 (3H, s), 6.26 (2H, s), 6.49 (2H, s),7.11 (1H, s), 7.30 (1H, d, J=8.4 Hz), 7.51 (1H, t, J=4.9 Hz), 7.94 (1H,d, J=8.4 Hz), 8.78-9.04 (3H, m); LC-MS: m/z=+458.10 (M+H)+.

Example 98 Preparation of(2R)-4-[1-(2-amino-6-methylpyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-olMono Formate Salt

Step 1—Synthesis of4-(6-bromo-3-methyl-1H-indazol-1-yl)-6-methylpyrimidin-2-amine

To a solution of 6-bromo-3-methyl-1H-indazole (500 mg, 2.37 mmol) in dryDMF (5 mL) at 0° C. under an atmosphere of nitrogen was introducedsodium hydride (684 mg of a 60% dispersion in mineral oil, 7.11 mmol).After warming to RT for 30 minutes, 4-chloro-6-methylpyrimidin-2-amine(510 mg, 3.55 mmol) was added and the solution warmed to 65° C. for 18hr. The reaction mixture was cooled to RT, quenched by dropwise additionof water (5 mL) and extracted with 2:1-chloroform/isopropanol (3×10 mLextractions). The combined organic extracts were washed with water (5mL) and brine (5 mL), dried (Na₂SO₄), filtered and concentrated invacuo. Purification of the residue by column chromatography (Biotage,DCM containing a 0-10% gradient of methanol) furnished a yellowsemi-solid which was slurried in acetonitrile (3 mL). The precipitatewas collected by filtration to furnish the title compound as a yellowsolid: ¹H NMR (500 MHz, DMSO) delta 2.29 (3H, s), 2.56 (3H, s),6.79-6.93 (2H, m), 6.93-6.95 (1H, m), 7.48 (1H, dd, J=8.43, 1.66 Hz),7.78 (1H, d, J=8.35 Hz), 9.07 (1H, d, J=1.42 Hz); LC-MS:m/z=+317.95/319.95.

Step 2—Synthesis of(2R)-4-[1-(2-amino-6-methylpyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-olMono Formate Salt

To a solution of4-(6-bromo-3-methyl-1H-indazol-1-yl)-6-methylpyrimidin-2-amine (100 mg,0.29 mmol) in piperidine (1 mL) was introducedtetrakis(triphenylphosphine)palladium (0) (27 mg, 0.02 mmol), copper(I)iodide (5 mg, 0.02 mmol) and(2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (89 mg, 0.58 mmol).The reaction mixture was warmed to 66° C. for 2 hr. After cooling to RT,the reaction mixture was concentrated in vacuo, DCM (10 mL) was addedand the solution re-evaporated to dryness in vacuo (re-evaporationprocess repeated twice). Purification of the residue by columnchromatography (Biotage, DCM containing a 0-10% gradient of methanol)furnished a brown oil which was suspended in acetonitrile andconcentrated in vacuo. The residue was re-suspended in acetonitrile (1mL), whereupon a brown solid precipitated and was collected byfiltration. Further purification by reverse phase preparative HPLCfurnished the title compound as a pink solid: ¹H NMR (500 MHz, DMSO)delta 1.89 (3H, s), 2.29 (3H, s), 2.57 (3H, s), 2.62 (3H, s), 6.66-6.92(3H, m), 6.96 (1H, s), 7.34 (1H, dd, J=8.20, 1.10 Hz), 7.84 (1H, d,J=8.20 Hz), 8.18 (1H, br. s.), 8.86 (1H, s); LC-MS: m/z=+390.05 (M+H)+.

Example 99 Preparation of4-[1-(2-amino-6-methylpyrimidin-4-yl)-3-methyl-1H-indazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-olMono Formate Salt

To a solution of4-(6-bromo-3-methyl-1H-indazol-1-yl)-6-methylpyrimidin-2-amine (191 mg,0.56 mmol) in piperidine (2 mL) was introducedtetrakis(triphenylphosphine)palladium (0) (52 mg, 0.05 mmol), copper(I)iodide (58.5 mg, 0.05 mmol) and 2-(pyrimidin-2-yl)but-3-yn-2-ol (171 mg,1.12 mmol). The reaction mixture was warmed to 66° C. for 2 hr. Aftercooling to RT, the reaction mixture was concentrated in vacuo, DCM (10mL) was added and the solution re-evaporated to dryness in vacuo(re-evaporation process repeated twice). Purification of the residue bycolumn chromatography (Biotage, DCM containing a 0-10% gradient ofmethanol) furnished a brown oil which was suspended in acetonitrile andconcentrated in vacuo. The residue was re-suspended in acetonitrile (1mL), whereupon a brown solid precipitated and was collected byfiltration. Further purification by reverse phase preparative HPLCfurnished the title compound as a colorless solid: ¹H NMR (500 MHz,CHLOROFORM-d) delta 2.06 (3H, s), 2.41 (3H, s), 2.59 (3H, s), 5.41 (2H,br. s.), 7.16 (1H, s), 7.31-7.38 (2H, m), 7.55 (1H, d, J=8.20 Hz), 8.83(1H, s), 8.85 (2H, d, J=4.89 Hz); LC-MS: m/z=+386.05 (M+H)+.

Example 100 Preparation of(2R)-4-[1-(2-amino-5-chloropyrimidin-4-yl)-3-[(4-fluoropiperidin-1-yl)carbonyl]-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-olMono Formate Salt

Step 1—Synthesis of1-(2-amino-5-chloropyrimidin-4-yl)-6-iodo-1H-indazole-3-carboxylic Acid

To a solution of 6-iodo-1H-indazole-3-carboxylic acid (300 mg, 1.04mmol) in dry DMF (68 mL) at 0° C. under an atmosphere of nitrogen wasintroduced sodium hydride (100 mg of a 60% dispersion in mineral oil,2.5 mmol). After 10 minutes at this temperature,4,5-chloropyrimidin-2-amine (342 mg, 2.08 mmol) was added and thesolution warmed to RT for 30 minutes, then to 65° C. for 18 hr. Thereaction mixture was cooled to RT, quenched carefully by pouring intoice-water (50 mL) and the resulting precipitate collected by filtration.Following adjustment of the pH to 7 by addition of 2M aqueoushydrochloric acid, the filtrate was extracted with DCM (3×10 mLextraction) and 3:1 chloroform/isopropanol (3×10 mL extractions), andthe combined extracts dried (Na₂SO₄) and concentrated in vacuo. Thefiltrate residue was combined with the precipitate to furnish the crudetitle compound as a tan solid: ¹H NMR (500 MHz, DMSO) delta 7.34 (2H,s), 7.68 (1H, d, J=8.3 Hz), 8.04 (1H, d, J=8.4 Hz), 8.63-8.42 (2H, m);LC-MS: m/z=+415.85/417.55 (M+H)+. This compound, with LC-MS purity=58%UV, was used in the next step without further purification.

Step 2—Synthesis of1-(2-amino-5-chloropyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-yn-1-yl]-1H-indazole-3-carboxylicAcid

To a solution of1-(2-amino-5-chloropyrimidin-4-yl)-6-iodo-1H-indazole-3-carboxylic acid(400 mg at 58% purity, 0.56 mmol) in piperidine (3 mL) was introducedtetrakis(triphenylphosphine)palladium (0) (111 mg, 0.10 mmol), copper(I)iodide (18.3 mg, 0.10 mmol) and(2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (293 mg, 1.93 mmol).The reaction was warmed to 35° C. under an atmosphere of nitrogen for 1hr. After cooling to RT, the reaction mixture was concentrated in vacuoand the residue purified by silica gel flash column chromatography(eluent: DCM containing a 1-15% MeOH gradient followed by 85:15 DCM:7Mammonia in methanol). The partially purified compound was dissolved inDCM (20 mL) and washed with 2M aqueous citric acid (10 mL). The organicphase was dried (Na₂SO₄), filtered and concentrated in vacuo to furnishthe title compound as a dark oil: ¹H NMR (500 MHz, DMSO) delta 1.86 (3H,s), 2.62 (3H, s), 6.80 (1H, s), 7.53-7.35 (3H, m), 8.09 (1H, s), 8.23(1H, d, J=8.4 Hz), 8.56 (1H, s); LC-MS: m/z=+439.90/441.90 (M+H)+. Thiscompound, with LC-MS purity=61% UV, was used in the next step withoutfurther purification.

Step 3—Synthesis of(2R)-4-[1-(2-amino-5-chloropyrimidin-4-yl)-3-[(4-fluoropiperidin-1-yl)carbonyl]-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-olMono Formate Salt

To a solution of1-(2-amino-5-chloropyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-yn-1-yl]-1H-indazole-3-carboxylicacid (120 mg at 61% purity, 0.17 mmol) in DMF (3 mL) was introducedO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (127 mg, 0.33 mmol), 4-fluoropiperidinehydrochloride (47 mg, 0.33 mmol) and triethylamine (0.07 mL, 0.5 mmol).After 2 hr at RT, the reaction mixture was diluted with water (2 ml) andextracted with EtOAc (2×5 mL extractions). The combined organic extractswere washed with water (5 mL) and brine (5 ml), dried (Na₂SO₄), filteredand concentrated in vacuo. Purification of the residue by reverse phasepreparative HPLC furnished the title compound as an off-white solid: ¹HNMR (DMSO, 500 MHz) delta 1.76-1.91 (5H, m), 1.95-2.06 (2H, m), 2.62(3H, s), 3.73-3.85 (2H, m), 4.01 (2H, t, J=5.4 Hz), 4.89-5.06 (1H, m),6.82 (1H, s), 7.33-7.52 (3H, m), 8.05 (1H, d, J=8.3 Hz), 8.27 (1H, s),8.54 (1H, s); LC-MS: m/z=+525.10/526.75.

Example 101 Preparation of(2R)-4-[1-(2-amino-5-chloropyrimidin-4-yl)-3-[(piperidin-1-yl)carbonyl]-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-olMono Formate Salt

The title compound was isolated by reverse phase preparative HPLC fromthe synthesis described for(2R)-4-[1-(2-amino-5-chloropyrimidin-4-yl)-3-[(4-fluoropiperidin-1-yl)carbonyl]-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-olmono formate salt, as a side product due the presence of piperidineimpurity in the starting material. The title compound was furnished as apale yellow solid: ¹H NMR (DMSO, 500 MHz) delta 1.51-1.73 (6H, m), 1.87(3H, s), 2.62 (3H, s), 3.66-3.79 (2H, m), 3.83-3.90 (2H, m), 6.82 (1H,s), 7.23-7.62 (3H, m), 8.01 (1H, d, J=8.5 Hz), 8.26 (1H, s), 8.53 (1H,s); LC-MS: m/z=+507.10/508.80 (M+H)+.

Example 102 Preparation of1-{[1-(2-amino-5-chloropyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-yn-1-yl]-1H-indazol-3-yl]carbonyl}azetidin-3-ol

Step 1—Synthesis of1-(2-amino-5-chloropyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-yn-1-yl]-1H-indazole-3-carboxylicAcid

To a solution of1-(2-amino-5-chloropyrimidin-4-yl)-6-iodo-1H-indazole-3-carboxylic acid(400 mg, 0.96 mmol) in piperidine (4 mL) was introducedtetrakis(triphenylphosphine)palladium (0) (111 mg, 0.10 mmol), copper(I)iodide (18.3 mg, 0.10 mmol) and(2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (292 mg, 1.92 mmol).The reaction was warmed to 35° C. for 1 hr. After cooling to RT, thereaction mixture was concentrated in vacuo and the residue purified bysilica gel flash column chromatography (eluent: DCM containing a 1-15%MeOH gradient followed by 85:15 DCM:7M ammonia in methanol). Thepartially purified compound was dissolved in DCM (20 mL) and washed with2M aqueous citric acid (10 mL). The organic phase was dried (Na₂SO₄),filtered and concentrated in vacuo to furnish the title compound as adark oil: ¹H NMR (500 MHz, DMSO) delta 1.86 (3H, s), 2.62 (3H, s), 6.80(1H, s), 7.53-7.35 (3H, m), 8.09 (1H, s), 8.23 (1H, d, J=8.4 Hz), 8.56(1H, s); LC-MS: m/z=+439.90 (M+H)+. This compound, with LC-MS purity=65%UV, was used in the next step without further purification.

Step 2—Synthesis of1-{[1-(2-amino-5-chloropyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-yn-1-yl]-1H-indazol-3-yl]carbonyl}azetidin-3-ol

To a solution of1-(2-amino-5-chloropyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-yn-1-yl]-1H-indazole-3-carboxylicacid (100 mg at 65% purity, 0.14 mmol) in DMF (3 mL) was introducedO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (105 mg, 0.28 mmol), azetidin-3-ol hydrochloride (30mg, 0.28 mmol) and triethylamine (0.06 mL, 0.42 mmol). After 5 hr at RT,the reaction mixture was retreated withO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (105 mg, 0.28 mmol), azetidin-3-ol hydrochloride (30mg, 0.28 mmol) and triethylamine (0.06 mL, 0.42 mmol). The reaction wasgiven a further 1 hr at RT, then diluted with water (2 ml) and extractedwith EtOAc (2×5 mL extractions). The combined organic extracts werewashed with water (5 mL) and brine (5 ml), dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the residue by silica gel flashcolumn chromatography (DCM containing a 2-12% gradient of methanol)furnished a solid which was suspended in acetonitrile (2 mL). Filtrationfurnished the title compound as a colorless solid: ¹H NMR (500 MHz,DMSO-d6) delta 1.86 (3H, s), 2.62 (3H, s), 3.85 (1H, dd, J=10.9, 4.1Hz), 4.19-4.45 (2H, m), 4.45-4.67 (1H, m), 4.71-4.97 (1H, m), 5.80 (1H,s), 6.76 (1H, s), 7.26-7.58 (3H, m), 8.02-8.35 (2H, m), 8.54 (1H, s);LC-MS: m/z=+495.05/497.10 (M+H)+.

Example 103 Preparation of(2R)-4-[1-(2-amino-5-chloropyrimidin-4-yl)-3-(2-hydroxypropan-2-yl)-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

Step 1—Synthesis of2-[1-(2-amino-5-chloropyrimidin-4-yl)-6-iodo-1H-indazol-3-yl]propan-2-ol

To a solution of 2-(6-iodo-1H-indazol-3-yl)propan-2-ol (300 mg, 0.99mmol) in dry DMF (10 mL) at 0° C. under an atmosphere of nitrogen wasintroduced sodium hydride (63 mg of a 60% dispersion in mineral oil,1.59 mmol). After 20 minutes at this temperature,4,5-dichloropyrimidin-2-amine (326 mg, 1.99 mmol) was added and thesolution warmed to RT for 10 minutes, then to 65° C. for 18 hr.Following cooling to RT, the reaction mixture was re-treated withadditional sodium hydride (24 mg of a 60% dispersion in mineral oil)then warmed to 75° C. under nitrogen for 6 hr. The reaction mixture wascooled to RT, quenched carefully with water (20 mL) and extracted withEtOAc (2×20 mL extractions). The organic extracts were combined, dried(MgSO₄), filtered and concentrated in vacuo. Purification of the residueby silica gel flash column chromatography (4:1 to 1:1 heptane/EtOAcgradient) furnished the title compound as an off-white solid: ¹H NMR(500 MHz, CDCl₃) delta 1.79 (6H, s), 5.19 (2H, br. s.), 7.61 (1H, dd,J=8.35, 1.42 Hz), 7.76 (1H, d, J=8.51 Hz), 8.42 (1H, s), 8.64 (1H, d,J=0.95 Hz); LC-MS: m/z=+429.90/431.65 (M+H)+.

Step 2—Synthesis of(2R)-4-[1-(2-amino-5-chloropyrimidin-4-yl)-3-(2-hydroxypropan-2-yl)-1H-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

To a solution of2-[1-(2-amino-5-chloropyrimidin-4-yl)-6-iodo-1H-indazol-3-yl]propan-2-ol(150 mg, 0.35 mmol) in piperidine (2 mL) was introducedtetrakis(triphenylphosphine)palladium (0) (40.3 mg, 0.02 mmol),copper(I) iodide (6.6 mg, 0.02 mmol) and(2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (106 mg, 0.70 mmol).The reaction was warmed to 35° C. for 1.5 hr. After cooling to RT, thereaction mixture was concentrated in vacuo and the residue purified bysilica gel flash column chromatography (heptane/EtOAc gradient) tofurnish the title compound as a dark red solid: ¹H NMR (500 MHz,DMSO-d6) delta 1.69 (6H, s), 1.93 (3H, s), 2.69 (3H, s), 5.65 (1H, s),6.85 (1H, s), 7.34 (2H, br. s.), 7.39 (1H, dd, J=8.35, 1.10 Hz), 8.21(1H, d, J=8.35 Hz), 8.26 (1H, s), 8.51 (1H, s); LC-MS:m/z=+454.05/456.05 (M+H)+.

Example 104 Preparation of4-{1-[2-amino-5-(1-methylpyrazol-4-yl)pyrimidin-4-yl]indazol-6-yl}-2-methylbut-3-yn-2-ol

5-bromo-4-(6-bromoindazol-1-yl)pyrimidin-2-amine (3 g) was reacted with2-methyl-3-butyn-2-ol (1 eq) via Sonagashira Coupling to afford 0.7 g of4-[1-(2-amino-5-bromo-pyrimidin-4-yl)indazol-6-yl]-2-methyl-but-3-yn-2-olfollowing flash column chromatography.4-[1-(2-amino-5-bromo-pyrimidin-4-yl)indazol-6-yl]-2-methyl-but-3-yn-2-ol(0.1 g) was reacted with 1-methyl-4-pyrazoleboronic acid pinacol estervia Suzuki Coupling to afford 12.2 mg of4-[1-[2-amino-5-(1-methylpyrazol-4-yl)pyrimidin-4-yl]indazol-6-yl]-2-methyl-but-3-yn-2-olfollowing reverse phase hplc purification. MS (Q1) 374. ¹H NMR (400 MHz,DMSO) delta 8.57 (s, 1H), 8.30 (s, 1H), 7.88-7.81 (m, 2H), 7.48 (s, 1H),7.24 (dd, J=8.3, 1.1 Hz, 1H), 7.05 (s, 2H), 6.98 (s, 1H), 5.47 (s, 1H),3.73 (s, 3H), 1.48 (s, 6H).

Example 105 Preparation of4-{1-[2-amino-5-(1H-pyrazol-4-yl)pyrimidin-4-yl]indazol-6-yl}-2-methylbut-3-yn-2-ol

4-[1-(2-amino-5-bromo-pyrimidin-4-yl)indazol-6-yl]-2-methyl-but-3-yn-2-ol(0.075 g) was reacted 1-Boc-4-pyrazoleboronic acid pinacol ester viaSuzuki Coupling to afford 9.5 mg of4-[1-[2-amino-5-(1-methylpyrazol-4-yl)pyrimidin-4-yl]indazol-6-yl]-2-methyl-but-3-yn-2-olfollowing reverse phase hplc purification. MS (Q1) 360. ¹H NMR (400 MHz,DMSO) delta 12.71 (s, 1H), 8.62 (s, 1H), 8.30 (s, 1H), 7.84 (d, J=8.3Hz, 1H), 7.76 (s, 1H), 7.46 (s, 1H), 7.23 (d, J=8.2 Hz, 1H), 7.02 (s,2H), 5.45 (s, 1H), 1.47 (s, 6H).

Example 106 Preparation of4-(1-{6-[(2-methoxypyridin-3-yl)amino]pyrimidin-4-yl}-1H-indazol-6-yl)-2-methylbut-3-yn-2-ol

Step 1—Synthesis of 6-chloro-N-(2-methoxypyridin-3-yl)pyrimidin-4-amine

To a solution of 4,6-dichloropyrimidine (660.04 mg, 4.43 mmol) in1-butanol (10 mL) was added DIPEA (0.67 ml, 4.03 mmol) followed by2-methoxypyridin-3-amine (500 mg, 4.03 mmol). The reaction mixture wasthen heated to 90° C. for 2 hr. The reaction mixture was thenconcentrated in vacuo and partitioned between DCM and water. Aprecipitate was removed by filtration and the organics extracted (2×20ml DCM). The combined organic extracts were then washed with 0.5M HCl (5ml) and then dried (Na₂SO₄), filtered and concentrated in vacuo to givethe title intermediate (300 mg, LC-MS purity=83%); LC-MS:m/z=+236.95/238.90 (M+H)+.

Step 2—Synthesis of6-(6-iodoindazol-1-yl)-N-(2-methoxypyridin-3-yl)pyrimidin-4-amine

To a solution of 6-iodo-1H-indazole (100 mg, 0.41 mmol) in DMF (5 mL)was added NaH (60% oil dispersion, 32.78 mg, 0.82 mmol)) at 0° C. Thereaction mixture was stirred at 0° C. for 10 minutes before the additionof 6-chloro-N-(2-methoxypyridin-3-yl)pyrimidin-4-amine (126.7 mg, 0.55mmol). The reaction mixture was then stirred at 110° C. for 18 hr. Thereaction mixture was then cooled to RT, quenched by the addition ofwater (2 ml), EtOAc (a few drops) was added and the resultantprecipitate was collected by suction filtration and thoroughly driedunder high vacuum to give the title compound (120 mg, LC-MS:m/z=+444.90). This compound of 62% purity LC-MS (UV) was used withoutfurther purification.

Step 3—Synthesis of4-(1-{6-[(2-methoxypyridin-3-yl)amino]pyrimidin-4-yl}-1H-indazol-6-yl)-2-methylbut-3-yn-2-ol

To a pressure tube was added6-(6-iodoindazol-1-yl)-N-(2-methoxypyridin-3-yl)pyrimidin-4-amine (120mg, 0.27 mmol) followed by triethylamine (2 mL) and THF (2 mL). Next,copper(I) iodide (5.15 mg, 0.027 mmol),bis(triphenylphosphine)palladium(II) chloride (18.96 mg, 0.027 mmol) and2-methylbut-3-yn-2-ol (0.05 ml, 0.54 mmol) were added and the reactionvessel was sealed and stirred at RT for 1 h. The reaction mixture wasconcentrated in vacuo and DCM (5 ml) was added. The organics were washedwith 0.5M HCl (2×3 ml), water (3 ml) and brine (3 ml), and dried(Na₂SO₄), filtered and concentrated in vacuo. The crude product waspurified by flash chromatography (Isolute column, 4:6 to 1:1EtOAc:heptanes) to surrender the title compound as a white solid: ¹H NMR(500 MHz, CDCl₃) delta 1.69 (6H, s), 2.08 (1H, br. s.), 4.07 (3H, s),6.99 (1H, dd, J=7.80, 4.97 Hz), 7.32-7.41 (2H, m), 7.69 (1H, d, J=8.20Hz), 7.88 (1H, dd, J=4.97, 1.66 Hz), 8.19 (1H, s), 8.54-8.61 (1H, m),8.77 (1H, s), 8.99 (1H, s); LC-MS: m/z=+401.10 (M+H)+.

Example 107 Preparation of4-[1-(6-aminopyrimidin-4-yl)-1H-indazol-6-yl]-2-methylbut-3-yn-2-ol

Step 1—Synthesis of 6-(6-iodoindazol-1-yl)pyrimidin-4-amine

To a solution of 6-iodoindazole (500 mg, 2.05 mmol) in DMF (8 mL) wasadded NaH (60% oil dispersion, 131.12 mg, 3.28 mmol) at 0° C. Themixture was stirred at 0° C. to RT for 10 minutes before addition of6-chloropyrimidin-4-amine (477.78 mg, 3.69 mmol) and stirring at 60° C.for 17 hr and then transferred to a pressure tube and heated at 70° C.for a further 6 hr. The reaction mixture was cooled and quenched by theaddition of water (10 ml) and EtOAc (a few drops) was added. Theresultant precipitate was collected by suction filtration and thenthoroughly dried under high vacuum to give the title intermediate (248mg): LC-MS: m/z=+338.20 (M+H)+.

Step 2-Synthesis of4-[1-(6-aminopyrimidin-4-yl)-1H-indazol-6-yl]-2-methylbut-3-yn-2-ol

The title compound was prepared by the procedure described in Example1-b by reacting 6-(6-iodomoindazol-1-yl)pyrimidin-4-amine with2-methylbut-3-yn-2-ol: ¹H NMR (500 MHz, DMSO) delta 1.50 (6H, s), 5.56(1H, s), 6.95 (1H, s), 7.10 (2H, br. s.), 7.29 (1H, dd, J=8.20, 1.26Hz), 7.86 (1H, d, J=8.20 Hz), 8.46 (2H, d, J=9.30 Hz), 8.81 (1H, s);LC-MS: m/z=+294.50.

Example 108 Examples in Table 11 were prepared by procedure described inExample 14-e by reacting4-(6-bromo-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine with theappropriate but-3-yn-2-ol

TABLE 11 LCMS No Structure Name ¹H NMR (M + H) T11-108.1

4-[1-(2-aminopyrimidin-4- yl)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol- 3-yl)but-3-yn-2-ol (500 MHz, DMSO) delta1.84 (3H, s), 2.41 (3H, s), 6.39 (1H, d, J = 0.79 Hz), 6.49 (1H, s),7.07-7.25 (3H, m), 7.39 (1H, dd, J = 8.35, 1.58 Hz), 7.75 (1H, d, J =8.20 Hz), 8.39 (1H, br. s.), 8.58 (1H, d, J = 0.95 Hz), 9.09 (1H, s)361.05 T11-108.2

4-[1-(2-aminopyrimidin-4- yl)-1H-1,3-benzodiazol-6-yl]-2-(3-methyl-1,2-oxazol- 5-yl)but-3-yn-2-ol (500 MHz, DMSO) delta1.84 (3H, s), 2.25 (3H, s), 6.42 (1H, s), 6.71 (1H, s), 7.22-7.11 (3H,m), 7.43 (1H, d, J = 8.2 Hz), 7.76 (1H, d, J = 8.1 Hz), 8.41 (1H, s),8.62 (1H, s), 9.12 (1H, s). 361.5  T11-108.2

4-[1-(2-aminopyrimidin-4- yl)-1H-1,3-benzodiazol-6- yl]-2-(1H-pyrazol-4-yl)but-3-yn-2-ol (500 MHz, DMSO) delta 1.86 (3H, s), 5.95 (1H, s),7.16-7.28 (3H, m), 7.47 (1H, dd, J = 8.35, 1.58 Hz), 7.75 (2H, br. s.),7.80 (1H, d, J = 8.20 Hz), 8.45 (1H, d, J = 5.52 Hz), 8.64 (1H, d, J =0.79 Hz), 9.14 (1H, s), 12.76 (1H, br. s.) 346.0  T11-108.3

4-[1-(2-aminopyrimidin-4- yl)-1H-1,3-benzodiazol-6-yl]-2-cyclopropylbut- 3-yn-2-ol (500 MHz, DMSO) delta 0.42 (2H, tdd, J =8.63, 8.63, 5.12, 3.47 Hz), 0.47-0.53 (1H, m), 0.53-0.61 (1H, m),1.11-1.21 (1H, m), 1.54 (3H, s), 5.33 (1H, s), 7.07-7.17 (3H, m), 7.33(1H, dd, J = 8.20, 1.58 Hz), 7.69- 7.74 (1H, m), 8.38 (1H, d, J = 5.67Hz), 8.52 (1H, d, J = 0.95 Hz), 9.06 (1H, s) 320.05 T11-108.4

4-[1-(2-aminopyrimidin-4- yl)-1H-1,3-benzodiazol- 6-yl]-1-fluoro-2-methylbut-3-yn-2-ol (500 MHz, MeOD) delta 1.59 (3H, d, J = 1.89 Hz),4.31-4.49 (2H, m), 7.06 (1H, d, J = 5.52 Hz), 7.45 (1H, d, J = 8.35 Hz),7.69 (1H, d, J = 8.35 Hz), 8.36 (1H, d, J = 5.52 Hz), 8.58 (1H, s), 8.95(1H, s) 312.05

Examples 109

Examples in Table 12 were prepared by adaptation of procedure describedin Example 21 by substituting 2-(1,3-thiazol-2-yl)but-3-yn-2-ol with theappropriate but-3-yn-2-ol.

TABLE 12 LC-MS No Structure Name ¹H NMR (M + H) T12-109.1

1-(2-aminopyrimidin-4- yl)-6-[(3R)-3-hydroxy- 3-(1,3-thiazol-2-yl)but-1-yn-1-yl]-2,3-dihydro- 1H-1,3-benzodiazol- 2-one (500 MHz, DMSO) delta1.89 (3H, s), 6.91 (2H, s), 6.94 (1H, s), 7.04 (1H, d, J 8.1), 7.20 (1H,dd, J = 8.1, 1.5 Hz), 7.38 (1H, d, J = 5.6 Hz), 7.67 (1H, d, J = 3.2Hz), 7.76 (1H, d, J = 3.2 Hz), 8.34-8.27 (2H, m), 11.57 (1H, s 378.95T12-109.2

1-(2-aminopyrimidin-4- yl)-6-[(3R)-3-hydroxy- 3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl]- 2,3-dihydro-1H-1,3- benzodiazol-2-one (250 MHz,DMSO) delta 1.81 (3H, s), 2.40 (3H, s), 6.38 (1H, s), 6.44 (1H, s), 6.95(2H, s), 7.04 (1H, d, J = 8.07 Hz), 7.21 (1H, dd, J = 8.07, 1.52 Hz),7.40 (1H, d, J = 5.63 Hz), 8.24-8.39 (2H, m), 11.59 (1H, s) 377.4 T12-109.3

1-(2-aminopyrimidin-4- yl)-6-{3-hydroxy-3-[5- (hydroxymethyl)-1,2-oxazol-3-yl]but-1-yn- 1-yl}-2,3-dihydro-1H- 1,3-benzodiazol-2-one (500MHz, DMSO) delta 1.83 (3H, s), 4.56 (2H, d, J = 5.7 Hz), 5.65 (1H, t, J= 6.0 Hz), 6.56-6.43 (2H, m), 6.94 (2H, s), 7.05 (1H, d, J = 8.0 Hz),7.22 (1H, dd, J = 8.1, 1.5 Hz), 7.40 (1H, d, J = 5.6 Hz), 8.30 (1H, d, J= 5.6 Hz), 8.33 (1H, d, J = 1.1 Hz), 11.08 (1H, s). 393.0 

Example 110 Preparation of3-(2-aminopyrimidin-4-yl)-5-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl]-1-methyl-2,3-dihydro-1H-1,3-benzodiazol-2-one

Step 1—Synthesis of3-(2-aminopyrimidin-4-yl)-5-bromo-1-methyl-2,3-dihydro-1H-1,3-benzodiazol-2-one

To a solution of1-(2-aminopyrimidin-4-yl)-6-bromo-2,3-dihydro-1H-1,3-benzodiazol-2-one(500 mg, 1.63 mmol) in DMF (10 ml) at 0° C. was added sodium hydride(60% oil suspension, 65.33 g, 1.63 mmol). The reaction mixture wasallowed to warm to RT over 5 minutes before addition of iodomethane (0.1ml, 1.63 mmol) and stirring for 30 minutes. The mixture was quenched byaddition of water (5 mL), EtOAc was then added resulting in formation ofa precipitate. The precipitate was collected by suction filtration. Thefiltrate was extracted with EtOAc (×2). The combined organic fractionswere washed with water and dried (Na₂SO₄), filtered and concentrated invacuo. Combining the extract residue and the precipitate gave the crudetitle compound (600 mg); ¹H NMR (500 MHz, CDCl₃) delta 3.23 (3H, s),5.55 (2H, s), 6.72 (1H, d, J=8.3 Hz), 7.20-7.04 (1H, m), 7.42 (1H, d,J=5.7 Hz), 8.12 (1H, d, J=5.7 Hz), 8.39 (1H, d, J=1.8 Hz); LC-MS:m/z=+321.8 (M+H)+.

Step 2—Synthesis of3-(2-aminopyrimidin-4-yl)-5-[(3R)-3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl]-1-methyl-2,3-dihydro-1H-1,3-benzodiazol-2-one

The title compound was prepared by the method described in Step 2 ofExample 142-b by reacting3-(2-aminopyrimidin-4-yl)-5-bromo-1-methyl-2,3-dihydro-1H-1,3-benzodiazol-2-onewith (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol: ¹H NMR (500 MHz,DMSO) delta 1.82 (3H, s), 2.40 (3H, s), 3.38 (3H, s), 6.38 (1H, s), 6.44(1H, s), 6.97 (2H, s), 7.33-7.22 (2H, m), 7.42 (1H, d, J=5.6 Hz), 8.32(1H, d, J=5.6 Hz), 8.38 (1H, s); LC-MS: m/z=+391 (M+H)+.

Example 111

Examples in Table 13 were prepared by the procedure described in Example142-b by reacting3-(2-aminopyrimidin-4-yl)-5-bromo-1-methyl-2,3-dihydro-1H-1,3-benzodiazol-2-onewith the appropriate but-3-yn-2-ol intermediates.

TABLE 13 LC-MS No Structure Name ¹H NMR (M + H) T13-111.1

3-(2-aminopyrimidin-4- yl)-5-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol- 3-yl)but-1-yn-1-yl]-1- methyl-2,3-dihydro-1H-1,3-benzodiazol-2-one (500 MHz, CDCl₃) delta 2.06 (3H, s), 2.65 (3H, s),3.44 (3H, s), 4.54 (1H, br. s.), 5.42 (2H, s), 6.93 (1H, d, J = 8.20Hz), 7.34 (1H, dd, J = 8.04, 1.42 Hz), 7.70 (1H, d, J = 5.83 Hz), 8.35(1H, d, J = 5.83 Hz), 8.44 (1H, d, J = 1.10 Hz) 392   T13-111.2

3-(2-aminopyrimidin-4- yl)-5-(2-{7-hydroxy- 5H,6H,7H-pyrrolo[1,2-a]imidazol-7-yl}ethynyl)-1- methyl-2,3-dihydro-1H- 1,3-benzodiazol-2-one(500 MHz, DMSO) delta 2.72-2.84 (1H, m), 3.01-3.12 (1H, m), 3.30-3.36(3H, m), 3.99- 4.09 (2H, m), 6.47 (1H, s), 6.87-7.04 (3H, m), 7.09-7.15(1H, m), 7.26 (1H, d, J = 8.04 Hz), 7.32 (1H, dd, J = 8.04, 1.26 Hz),7.42 (1H, d, J = 5.52 Hz), 8.32 (1H, d, J = 5.67 Hz), 8.42 (1H, s)388.05

Example 112 Preparation of4-[1-(2-aminopyrimidin-4-yl)-2-ethoxy-1H-1,3-benzodiazol-6-yl]-2-methylbut-3-yn-2-ol

Step 1—Synthesis of4-(6-bromo-2-ethoxy-1,3-benzodiazol-1-yl)pyrimidin-2-amine

A mixture of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (652 mg,1.98 mmol), (triethoxymethoxy)ethane (2.0 mL, 9.89 mmol) and acetic acid(0.09 mL) was heated at 80° C. for 40 minutes. After cooling to roomtemperature, the mixture was concentrated in vacuo. The residue wasdissolved in ethyl acetate (5 mL) and washed with saturated aqueoussodium hydrogencarbonate (2×10 mL) and then brine. The organic layer wasdried over sodium sulfate, filtered and concentrated in vacuo to givethe crude product as an orange solid ¹H NMR (500 MHz, CDCl₃) delta 1.55(3H, t, J=7.09 Hz), 4.71 (2H, q, J=7.25 Hz), 5.21 (2H, br. s.), 7.13(1H, d, J=5.67 Hz), 7.35-7.42 (2H, m), 8.36-8.40 (2H, m); LC-MS:m/z=+334.00/335.75 (M+H)+.

Step 2—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-2-ethoxy-1H-1,3-benzodiazol-6-yl]-2-methylbut-3-yn-2-ol

The title compound was prepared by the procedure described in Step 2 ofExample 142-b by reacting4-(6-bromo-2-ethoxy-1,3-benzodiazol-1-yl)pyrimidin-2-amine with2-methyl-3-butyn-2-ol; ¹H NMR (500 MHz, MeOD) delta 1.54 (3H, t, J=7.09Hz), 1.58 (6H, s), 4.68 (2H, q, J=7.09 Hz), 7.11 (1H, d, J=5.67 Hz),7.25-7.32 (1H, m), 7.39 (1H, d, J=8.20 Hz), 8.29 (1H, s), 8.31-8.43 (1H,m); LC-MS: m/z=+338.5 (M+H)+.

Example 113

Examples in Table 14 are prepared by the procedures described in Example112-b, by reacting4-(6-bromo-2-ethoxy-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine with theappropriate but-3-yn-2-ol intermediates.

TABLE 14 LC-MS No Structure Name ¹H NMR (M + H) T14-113.1

4-[1-(2-aminopyrimidin-4- yl)-2-ethoxy-1H-1,3- benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3- yl)but-3-yn-2-ol (250 MHz, DMSO) delta 1.44 (3H, t,J = 7.01 Hz), 1.80 (3H, s), 2.39 (3H, s), 4.63 (2H, q, J = 7.11 Hz),6.36 (1H, d, J = 0.91 Hz), 6.44 (1H, s), 6.97 (1H, d, J = 5.48 Hz), 7.08(2H, s), 7.26 (1H, dd, J = 8.15, 1.60 Hz), 7.44 (1H, d, J = 8.22 Hz),8.14 (1H, d, J = 1.22 Hz), 8.38 (1H, d, J = 5.33 Hz) 405.45 T14-113.2

4-[1-(2-aminopyrimidin-4- yl)-2-ethoxy-1H-1,3- benzodiazol-6-yl]-2-[5-(hydroxymethyl)-1,2- oxazol-3-yl]but-3-yn-2-ol (500 MHz, DMSO) delta1.44 (3H, t, J = 7.1 Hz), 1.82 (3H, s), 4.55 (2H, d, J = 6.1 Hz), 4.63(2H, q, J = 7.1 Hz), 5.64 (1H, t, J = 6.0 Hz), 6.50 (2H, s), 6.97 (1H,d, J = 5.5 Hz), 7.08 (2H, s), 7.27 (1H, dd, J = 8.2, 1.4 Hz), 7.45 (1H,d, J = 8.2 Hz), 8.15 (1H, s), 8.38 (1H, d, J = 5.5 Hz). 421.05 T14-113.3

7-{2-[1-(2-aminopyrimidin- 4-yl)-2-ethoxy-1H-1,3-benzodiazol-6-yl]ethynyl}- 5H,6H,7H-pyrrolo[1,2- a]imidazol-7-ol (250MHz, DMSO) delta 1.45 (3H, t, J = 7.08 Hz), 2.77 (1H, br. s.), 2.92-3.11 (1H, m), 4.01-4.12 (2H, m), 4.64 (2H, q, J = 6.85 Hz), 6.92-7.02(2H, m), 7.09 (2H, s), 7.12 (1H, d, J = 1.07 Hz), 7.28 (1H, dd, J =8.15, 1.60 Hz), 7.46 (1H, d, J = 8.22 Hz), 8.18 (1H, d, J = 1.37 Hz),8.38 (1H, d, J = 5.48 Hz) 402.1 

Example 114 Preparation of7-{2-[1-(2-aminopyrimidin-4-yl)-2-ethoxy-1H-1,3-benzodiazol-6-yl]ethynyl}-5H,6H,7H-cyclopenta[b]pyridin-7-ol

Step 1—Synthesis of 4-N-(2-amino-5-iodophenyl)pyrimidine-2,4-diamine

A pressure tube containing copper(I) iodide (61.2 mg, 0.32 mmol), sodiumiodide (963.18 mg, 6.43 mmol) and4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (900 mg, 3.21 mmol)was flushed with nitrogen before the addition of 1,4-dioxane (4.0 mL),DMF (4.0 ml) and N,N′-dimethylethane-1,2-diamine (0.035 ml, 0.32 mmol).The vessel was sealed and stirred at 115° C. overnight. After cooling toRT, the reaction mixture was poured into ice water (7 ml) and theresulting solution extracted with DCM (2×100 mL). The combined organicswere dried (Na₂SO₄), filtered and concentrated in vacuo. Purification bycolumn chromatography (Biotage, 3-14% methanol gradient in DCM)furnished the title compound (600 mg, 57% yield); ¹H NMR (500 MHz, DMSO)delta 5.04 (2H, d, J=11.6 Hz), 5.78-5.73 (1H, m), 6.11-6.02 (2H, m),6.57 (1H, d, J=8.4 Hz), 7.18 (1H, dd, J=8.4, 2.0 Hz), 7.47-7.38 (1H, m),7.75 (1H, d, J=5.3 Hz), 8.20-8.12 (1H, m); LC-MS: m/z=+327.8 (M+H)+.

Step 2—Synthesis of4-(2-ethoxy-6-iodo-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine

The title compound was prepared by replacing4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine with4-N-(2-amino-5-iodophenyl)pyrimidine-2,4-diamine in the proceduredescribed in Example 112-a Step 1: ¹H NMR (500 MHz, DMSO) delta1.46-1.59 (3H, m), 4.63-4.77 (2H, m), 7.01-7.10 (1H, m), 7.17 (2H, br.s.), 7.36 (1H, d, J=8.35 Hz), 7.54-7.68 (1H, m), 8.43 (1H, d, J=5.52Hz), 8.58 (1H, d, J=1.58 Hz), 12.04 (1H, br. s.); LC-MS: m/z=+381.9(M+H)+.

Step 3—Synthesis of7-{2-[1-(2-aminopyrimidin-4-yl)-2-ethoxy-1H-1,3-benzodiazol-6-yl]ethynyl}-5H,6H,7H-cyclopenta[b]pyridin-7-ol

A mixture of4-(2-ethoxy-6-iodo-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine (150 mg,0.394 mmol) and 7-ethynyl-5H,6H-cyclopenta[b]pyridin-7-ol (118 mg, 0.59mmol) was dissolved in piperidine (1 mL). The solution was de-gassedwith nitrogen for 2 mins Tetrakis(triphenylphosphine)palladium(0) (36mg, 0.031 mmol) and copper(I) iodide (6 mg, 0.031 mmol) were added andthe resultant solution heated to 30° C. for 2 hr. The mixture wasconcentrated in vacuo, DCM (10 mL) added and re-concentrated in vacuo(twice). The residue was purified by column chromatography (Biotage,0-10% MeOH gradient in DCM), followed by reverse phase preparative HPLCpurification to give the title compound; ¹H NMR (500 MHz, DMSO) delta1.44 (3H, t, J=7.1 Hz), 2.36-2.42 (1H, m), 2.52-2.62 (1H, m), 2.83-2.95(1H, m), 2.94-3.08 (1H, m), 4.63 (2H, q, J=7.0 Hz), 6.96 (1H, d, J=5.5Hz), 7.08 (2H, s), 7.19-7.32 (2H, m), 7.44 (1H, d, J=8.2 Hz), 7.72 (1H,d, J=7.6 Hz), 8.13 (1H, s), 8.38 (1H, d, J=5.5 Hz), 8.44 (1H, d, J=4.8Hz), 8.51 (1H, s); LC-MS: m/z=+413.05 (M+H)+.

Example 115 Preparation of4-[1-(2-aminopyrimidin-4-yl)-2-ethoxy-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol

Step 1—Synthesis of4-{2-ethoxy-6-[2-(trimethylsilyl)ethynyl]-1H-1,3-benzodiazol-1-yl}pyrimidin-2-amine

To a solution of4-(6-bromo-2-ethoxy-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine (270 mg,0.74 mmol) in piperidine (1.8 mL) was introducedtetrakis(triphenylphosphine)palladium(0) (69 mg, 0.06 mmol), copper(I)iodide (11 mg, 0.06 mmol) and ethynyltrimethylsilane (0.53 mL, 3.71mmol). The reaction mixture was warmed to 65° C. for 3 hr. After coolingto RT, the reaction mixture was re-treated with furthertetrakis(triphenylphosphine)palladium(0) (10 mg, 0.01 mmol), copper(I)iodide (5 mg, 0.03 mmol), ethynyltrimethylsilane (0.20 mL, 1.4 mmol) andwarmed to 65° C. for an additional 2 hr. The reaction mixture wasconcentrated in vacuo and the residue re-dissolved in DCM (10 mL) andre-evaporated to dryness in vacuo (this procedure was repeated twice).Purification of the residue by column chromatography (Biotage, DCMcontaining a 2-8% gradient of methanol) furnished the title compound asan off-white solid: ¹H NMR (250 MHz, DMSO) delta −0.07-0.07 (9H, m),1.21 (3H, t, J=7.01 Hz), 4.40 (2H, q, J=7.06 Hz), 6.65-6.81 (1H, m),6.88 (2H, br. s.), 7.06 (1H, dd, J=8.15, 1.60 Hz), 7.20 (1H, d, J=8.22Hz), 7.98 (1H, d, J=1.22 Hz), 8.12-8.25 (1H, m); LCMS: m/z=+352.45(M+H)+.

Step 2—Synthesis of4-(2-ethoxy-6-ethynyl-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine

To a solution of4-{2-ethoxy-6-[2-(trimethylsilyl)ethynyl]-1H-1,3-benzodiazol-1-yl}pyrimidin-2-amine(170 mg, 0.48 mmol) in dry THF (5 mL) at RT was introduced TBAF (0.58 mLof a 1M solution in THF, 0.58 mmol). After 20 minutes, the reactionmixture was concentrated in vacuo, DCM (5 mL) added, and the solutionre-evaporated to dryness in vacuo (re-evaporation process repeatedtwice). Purification of the residue by column chromatography (Biotage,DCM containing a 1-7% gradient of methanol) furnished the title compoundas a beige solid: ¹H NMR (500 MHz, DMSO) delta 1.46 (3H, t, J=7.01 Hz),4.10 (1H, s), 4.61-4.68 (2H, m), 6.97-7.03 (1H, m), 7.09 (2H, br. s.),7.33 (1H, dd, J=8.12, 1.34 Hz), 7.45 (1H, d, J=8.04 Hz), 8.33 (1H, s),8.37 (1H, d, J=5.52 Hz); LC-MS: m/z=+280.00 (M+H)+.

Step 3—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-2-ethoxy-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol

To a solution of4-(2-ethoxy-6-ethynyl-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine (110 mg,0.37 mmol) in dry THF (1 mL) at −78° C. was introduced lithiumdiisopropylamide (0.47 mL of a 2M solution in THF, 0.935 mmol). After 5minutes, 1-pyrimidin-2-yl-ethanone (81 mg, 0.65 mmol) was added and thereaction mixture maintained at −78° C. for 20 minutes. Following 30minutes at RT, saturated aqueous ammonium chloride (0.5 ml) was addedand the solution concentrated in vacuo. The residue was dissolved in DCM(10 mL), washed with water (2 mL), dried (Na₂SO₄), filtered andconcentrated in vacuo. Purification of the residue by columnchromatography (Biotage, DCM containing a 0-8% gradient of methanol)furnished the title compound as a beige solid: ¹H NMR (500 MHz, DMSO)delta 1.44 (3H, t, J=7.09 Hz), 1.88 (3H, s), 4.63 (2H, q, J=7.09 Hz),6.14 (1H, s), 6.96 (1H, d, J=5.36 Hz), 7.09 (2H, br.s.), 7.22 (1H, dd,J=8.20, 1.58 Hz), 7.43 (1H, d, J=8.20 Hz), 7.49 (1H, t, J=4.81 Hz), 8.10(1H, d, J=1.10 Hz), 8.38 (1H, d, J=5.36 Hz), 8.88 (2H, d, J=4.89 Hz);LC-MS: m/z=+402.45 (M+H)+.

Example 116 Preparation of7-{2-[1-(2-aminopyrimidin-4-yl)-2-ethoxy-1H-1,3-benzodiazol-6-yl]ethynyl}-5H,6H,7H-cyclopenta[b]pyridin-7-olMono Formate Salt

To a solution of4-(2-ethoxy-6-iodo-1H-1,3-benzodiazol-1-yl)pyrimidin-2-amine (150 mg,0.39 mmol) in piperidine (2 mL) was introducedtetrakis(triphenylphosphine)palladium (0) (36.4 mg, 0.03 mmol),copper(I) iodide (6 mg, 0.03 mmol) and7-ethynyl-5H,6H,7H-cyclopenta[b]pyridin-7-ol (117 mg, 0.59 mmol). Thereaction was warmed to 30° C. for 2 hr. After the reaction mixture wasconcentrated in vacuo, DCM (5 mL) was added and the solutionre-evaporated to dryness in vacuo (re-evaporation process repeatedtwice). Purification of the residue by column chromatography (Biotage,DCM containing a 0-8% gradient of methanol) furnished a partiallypurified product. Further purification by reverse phase preparative HPLCfurnished the title compound as a yellow solid: ¹H NMR (500 MHz, DMSO)delta 1.44 (3H, t, J=7.1 Hz), 2.36-2.42 (1H, m), 2.52-2.62 (1H, m),2.83-2.95 (1H, m), 2.94-3.08 (1H, m), 4.63 (2H, q, J=7.0 Hz), 6.96 (1H,d, J=5.5 Hz), 7.08 (2H, s), 7.19-7.32 (2H, m), 7.44 (1H, d, J=8.2 Hz),7.72 (1H, d, J=7.6 Hz), 8.13 (1H, s), 8.38 (1H, d, J=5.5 Hz), 8.44 (1H,d, J=4.8 Hz), 8.51 (1H, s); LC-MS: m/z=+413.05 (M+H)+.

Example 117 Preparation of(2R)-4-[1-(2-aminopyrimidin-4-yl)-2-(oxetan-3-yloxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

Step 1—Synthesis of4-[6-bromo-2-(trichloromethyl)-1,3-benzodiazol-1-yl]pyrimidin-2-amine

To a solution of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (3.0g, 10.71 mmol) in acetic acid (10 mL) was added methyl2,2,2-trichloroethanimidoate (1.4 mL, 11.25 mmol). The reaction wasstirred at 45° C. for 7 hr. Water (15 mL) was then added. Theprecipitate was collected by filtration and dried under vacuum to givethe title product (3.94 g as the acetic acid salt); ¹H NMR (500 MHz,DMSO) delta 1.90 (3H, s), 7.01 (1H, d, J=5.0 Hz), 7.21 (2H, s),7.75-7.46 (2H, m), 8.09-7.75 (1H, m), 8.58 (1H, d, J=5.0 Hz); LC-MS:m/z=+406/408/410/412 (M+H)+.

Step 2-Synthesis of4-[6-bromo-2-(oxetan-3-yloxy)-1,3-benzodiazol-1-yl]pyrimidin-2-amine

To a solution of oxetan-3-ol (0.04 ml, 0.61 mmol) in DMF (5 ml) at 0° C.was added cesium carbonate (499.75 mg, 1.53 mmol) followed by4-[6-bromo-2-(trichloromethyl)-1,3-benzodiazol-1-yl]pyrimidin-2-amine(250 mg, 0.61 mmol). The reaction was stirred at RT overnight, thenre-charged with oxetan-3-ol (3 eq) and stirred for a total of 5 days atRT. Water was added (15 ml) to the combined reaction mixtures and theproduct extracted into DCM (2×30 ml). The combined organic extracts werewashed with water and brine (10 ml each), dried (Na₂SO₄), filtered andconcentrated in vacuo to give the title compound; ¹H NMR (500 MHz, DMSO)delta 4.83-4.70 (2H, m), 5.03-4.89 (2H, m), 5.85-5.75 (1H, m), 7.19-7.05(3H, m), 7.51-7.34 (2H, m), 8.40 (1H, d, J=5.5 Hz), 8.45 (1H, d, J=1.7Hz); LC-MS: m/z=+362/364 (M+H)+.

Step 3—Synthesis of(2R)-4-[1-(2-aminopyrimidin-4-yl)-2-(oxetan-3-yloxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

The title compound was prepared by the method described in Example142-b, by reacting4-[6-bromo-2-(oxetan-3-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-aminewith (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol: ¹H NMR (500 MHz,DMSO) delta 1.81 (3H, s), 2.40 (3H, s), 4.80-4.71 (2H, m), 4.96 (2H, t,J=7.1 Hz), 5.87-5.78 (1H, m), 6.37 (1H, s), 6.46 (1H, s), 7.22-7.04 (3H,m), 7.28 (1H, dd, J=8.2, 1.5 Hz), 7.45 (1H, d, J=8.2 Hz), 8.18 (1H, s),8.42 (1H, d, J=5.5 Hz); LC-MS: m/z=+433.15 (M+H)+.

Example 118 Preparation of4-[1-(2-aminopyrimidin-4-yl)-2-(oxetan-3-yloxy)-1H-1,3-benzodiazol-6-yl]-2-methylbut-3-yn-2-ol

The title compound was prepared by the method described in Example142-b, by reacting4-[6-bromo-2-(oxetan-3-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-aminewith 2-methyl-3-butyn-2-ol: ¹H NMR (DMSO, 500 MHz) delta 1.46 (6H, s),4.73 (2H, dd, J=7.9, 4.9 Hz), 4.94 (2H, t, J=7.1 Hz), 5.40 (1H, s),5.94-5.68 (1H, m), 7.17-6.99 (3H, m), 7.21 (1H, dd, J=8.2, 1.6 Hz), 7.41(1H, d, J=8.2 Hz), 8.14 (1H, d, J=1.0 Hz), 8.39 (1H, d, J=5.5 Hz);LC-MS: m/z=+366.1 (M+H)+.

Example 119 Preparation of(2R)-4-[1-(2-aminopyrimidin-4-yl)-2-(2-methoxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

Step 1—Synthesis of4-[6-bromo-2-(2-methoxyethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine

The title compound was prepared by the procedure described for thesynthesis of4-[6-bromo-2-(oxetan-3-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine,by replacing oxetan-3-ol with 2-methoxyethanol: ¹H NMR (500 MHz, DMSO)delta 3.31 (3H, s), 3.83-3.72 (2H, m), 4.77-4.61 (2H, m), 7.02 (1H, d,J=5.5 Hz), 7.12 (2H, s), 7.48-7.33 (2H, m), 8.38 (1H, d, J=5.5 Hz), 8.45(1H, d, J=1.8 Hz); LC-MS: m/z=+364/366 (M+H)+.

Step2-(2R)-4-[1-(2-aminopyrimidin-4-yl)-2-(2-methoxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

The title compound was prepared by the method described in Example142-b, by reacting4-[6-bromo-2-(2-methoxyethoxy)-1,3-benzodiazol-1-yl]pyrimidin-2-aminewith (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol: ¹H NMR (500 MHz,DMSO) delta 1.81 (3H, s), 2.41 (3H, s), 3.95-3.64 (2H, m), 4.84-4.63(2H, m), 6.38 (1H, s), 6.46 (1H, s), 6.98 (1H, d, J=5.5 Hz), 7.11 (2H,s), 7.28 (1H, dd, J=8.0, 1.2 Hz), 7.46 (1H, d, J=8.2 Hz), 8.18 (1H, s),8.40 (1H, d, J=5.4 Hz); LC-MS: m/z=+435.0 (M+H)+.

Example 120 Preparation of(2R)-4-[1-(2-aminopyrimidin-4-yl)-2-[(2-methoxyethyl)amino]-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

Step 1-Synthesis of1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-1,3-benzodiazol-2-amine

A mixture of 2-methoxyethanamine (5 mL) and4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(500 mg, 1.23 mmol) were stirred at RT for 3 days. The reaction mixturewas then concentrated in vacuo and EtOAc/heptane (2:1) added. Thesolvent was removed in vacuo and this was repeated (×2). The resultingsolid was then triturated from EtOAc:heptane (1:2). The solid was thendissolved in DCM (5 ml) and washed with water (2×2 ml). The organicphase was dried (Na₂SO₄), filtered and concentrated in vacuo to give thetitle compound (145 mg, 45% yield): ¹H NMR (500 MHz, DMSO) delta 3.28(3H, s), 3.71-3.53 (4H, m), 6.93 (1H, d, J=5.5), 7.14 (2H, s), 7.31-7.20(2H, m), 7.67 (1H, d, J=1.6), 8.13 (1H, t, J=5.3), 8.41 (1H, d, J=5.5);LC-MS: m/z+363/365 (M+H)+.

Step 2—Synthesis of(2R)-4-[1-(2-aminopyrimidin-4-yl)-2-[(2-methoxyethyl)amino]-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

The title compound was prepared by the method described in Example142-b, by reacting1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-1,3-benzodiazol-2-aminewith (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol: ¹H NMR (250 MHz,DMSO) delta 1.79 (3H, s), 2.40 (3H, s), 3.28 (3H, s), 3.72-3.53 (4H, m),6.35 (1H, s), 6.41 (1H, s), 6.91 (1H, d, J=5.5 Hz), 7.34-7.07 (4H, m),7.50 (1H, d, J=1.0 Hz), 8.23 (1H, t, J=5.5 Hz), 8.43 (1H, d, J=5.5 Hz);LC-MS: m/z=+434.15 (M+H)+.

Example 121 Preparation of4-[1-(2-aminopyrimidin-4-yl)-2-(2-methoxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol

Step 1—Synthesis of4-[6-iodo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine

The title compound was prepared by procedure described for4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine,by replacing 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine with4-N-(2-amino-5-iodophenyl)pyrimidine-2,4-diamine ¹H NMR (500 MHz, DMSO)delta 1.91 (3H, s), 7.01 (1H, d, J=5.1 Hz), 7.22 (2H, s), 7.77-7.69 (3H,m), 8.58 (1H, d, J=5.0 Hz), 11.97 (1H, s); LC-MS: m/z=+454/456/458(M+H)+.

Step 2—Synthesis of4-[6-iodo-2-(2-methoxyethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine

The title compound was prepared by the procedure described for thesynthesis of4-[6-bromo-2-(oxetan-3-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amineby reacting4-[6-iodo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-aminewith 2-methoxyethanol: LC-MS: m/z=+412 (M+H)+.

Step 3—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-2-(2-methoxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol

To a pressure tube was added4-[6-iodo-2-(2-methoxyethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(70%, 120 mg, 0.2 mmol) followed by piperidine (1.0 mL),tetrakis(triphenylphosphine)palladium(0) (23.61 mg, 0.02 mmol),copper(I) iodide (3.89 mg, 0.02 mmol) and2-(pyrimidin-2-yl)but-3-yn-2-ol (60.53 mg, 0.41 mmol). The reaction wascapped and stirred at RT for 1 h. The reaction mixture was concentratedin vacuo. The crude material was purified by flash column chromatography(1-10% MeOH gradient in DCM), followed by trituration withEtOAc/heptanes/DCM to give the title compound: ¹H NMR (500 MHz, DMSO)delta 1.88 (3H, s), 3.92-3.64 (2H, m), 4.84-4.59 (2H, m), 6.13 (1H, s),6.97 (1H, d, J=5.5 Hz), 7.10 (2H, s), 7.23 (1H, dd, J=8.2, 1.5 Hz), 7.44(1H, d, J=8.1 Hz), 7.49 (1H, t, J=4.8 Hz), 8.13 (1H, s), 8.39 (1H, d,J=5.5 Hz), 8.89 (2H, d, J=4.9 Hz); LC-MS: m/z=+432.05 (M+H)+.

Example 122 Preparation of(2R)-4-[1-(2-aminopyrimidin-4-yl)-2-(2-methoxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

The title compound was prepared by the procedure described for thesynthesis of4-[1-(2-aminopyrimidin-4-yl)-2-(2-methoxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol(Example 121-c), by reacting4-[6-iodo-2-(2-methoxyethoxy)-1,3-benzodiazol-1-yl]pyrimidin-2-aminewith (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol: ¹H NMR (500MHz, DMSO) delta 1.84 (3H, s), 2.61 (3H, s), 3.31 (3H, s), 3.84-3.69(2H, m), 4.76-4.63 (2H, m), 6.66 (1H, s), 6.97 (1H, d, J=5.5 Hz), 7.09(2H, s), 7.28 (1H, dd, J=8.2, 1.5 Hz), 7.46 (1H, d, J=8.2 Hz), 8.18 (1H,d, J=1.0 Hz), 8.39 (1H, d, J=5.5 Hz); LC-MS: m/z=+436.1 (M+H)+.

Example 123 Preparation of4-(3-(2-aminopyrimidin-4-yl)-2-(2,2,2-trifluoroethoxy)-3H-benzo[d]imidazol-5-yl)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol

Step 1: Synthesis of4-(6-bromo-2-(trichloromethyl)-1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine

To a solution of 4-N-(2-amino-5-bromophenyl)pyrimidine-2,4-diamine (16.5g, 58.90 mmol) in acetic acid (55 mL) was added methyl2,2,2-trichloroethanecarboximidate (11 g, 62.35 mmol) dropwise withstirring. The reaction mixture was stirred at room temperature for 3 hrand then at 45° C. overnight. The resulting solution was diluted with100 mL of water and the precipitate was collected by filtration. Thesolid was dried in a vacuum oven to give 19.5 g (81%) of4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amineas a light brown solid: ¹H NMR (300 MHz, DMSO) delta 8.58 (d, J=4.8 Hz,1H), 7.68 (t, J=4.5 Hz, 1H), 7.61-7.58 (m, 2H), 7.21 (s, 2H), 7.01 (d,J=5.1 Hz, 3H); LC-MS: m/z=+408 (M+H)+.

Step 2: Synthesis of4-(6-bromo-2-(2,2,2-trifluoroethoxy)-1H-benzo[d]imidazol-1-yl)pyrimidin-2-amine

A mixture of4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(500 mg, 1.23 mmol), 2,2,2-trifluoroethan-1-ol (500 mg, 5.00 mmol) andcesium carbonate (2.5 g, 7.67 mmol) in N,N-dimethylformamide (5 mL)placed in a 10-mL sealed tube maintained under nitrogen was irradiatedwith microwave radiation at 70° C. for 2 hr. The residue was purified ona C18 column (acetonitrile/water, 5:95-80:20) to yield 260 mg (46%) of4-[6-bromo-2-(2,2,2-trifluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amineas a yellow solid. LC-MS: m/z=+388 (M+H)+.

Step 3: Synthesis of4-(3-(2-aminopyrimidin-4-yl)-2-(2,2,2-trifluoroethoxy)-3H-benzo[d]imidazol-5-yl)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol

A mixture of 4-[6-bromo-2-(2,2,2-trifluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (120 mg, 0.31 mmol),2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (120 mg, 0.79 mmol) andbis(triphenylphosphine)palladium(II) dichloride (200 mg, 0.28 mmol) indimethylsulfoxide (2 mL) and triethylamine (1 mL) kept in a 10-mL vialunder nitrogen was irradiated with microwave radiation for 2 h at 70° C.The reaction mixture was concentrated in vacuo. The crude product (120mg) was purified by preparative HPLC to give 55 mg (39%) of4-[1-(2-aminopyrimidin-4-yl)-2-(2,2,2-trifluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-olas a light yellow solid: ¹H NMR (400 MHz, DMSO) delta 8.45 (d, J=5.2 Hz,1H), 8.17 (s, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.17(s, 2H), 6.86 (d, J=5.2 Hz, 1H), 6.46 (s, 1H), 6.38 (s, 1H), 5.37-5.30(m, 2H), 2.41 (s, 3H), 1.82 (s, 3H); LC-MS: m/z=+459 (M+H)+.

Example 124 Preparation of4-(3-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-3H-benzo[d]imidazol-5-yl)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol

Step 1—Synthesis of2-(1-(2-aminopyrimidin-4-yl)-6-bromo-1H-benzo[d]imidazol-2-yloxy)ethanol

A mixture of4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(1 g, 2.45 mmol), ethane-1,2-diol (15 mL) and cesium carbonate (3 g,9.18 mmol) was stirred overnight at room temperature and then dilutedwith 200 mL of water. The resulting solution was extracted with 2×200 mLof dichloromethane. The combined organic layers were washed with 3×200mL of water, dried over anhydrous sodium sulfate and concentrated undervacuum to afford 300 mg (34%) of2-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]ethan-1-olas a yellow solid. ¹H NMR (300 MHz, DMSO) delta 8.39 (d, J=5.4 Hz, 1H),8.30 (s, 1H), 7.51 (s, 2H), 7.09 (d, J=5.4 Hz, 1H), 4.78 (t, J=5.2 Hz,2H), 4.08 (t, J=4.2 Hz, 2H); LC-MS: m/z=+350 (M+H)+.

Step 2—Synthesis of4-(3-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-3H-benzo[d]imidazol-5-yl)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol

A solution of2-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]ethan-1-ol(80 mg, 0.19 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (80 mg,0.53 mmol), bis(triphenylphosphine)palladium(II) dichloride (20 mg, 0.03mmol) and triethylamine (0.7 mL) in dimethylsulfoxide (3 mL) undernitrogen in a 10-mL sealed tube was irradiated with microwave radiationfor 30 min at 70° C. The reaction mixture was concentrated and the crudeproduct (80 mg) was purified by Flash-Preparative HPLC to give 24 mg(28%) of4-[1-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-olas a yellow solid. ¹H NMR (400 MHz, DMSO-d6) delta 8.39 (d, J=5.6 Hz,1H), 8.19 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.06(s, 3H), 6.43 (s, 1H), 6.37 (s, 1H), 5.03 (t, J=5.2 Hz, 1H), 4.62 (s,2H), 3.82 (d, J=4.0 Hz, 2H), 2.41 (s, 3H), 1.81 (s, 3H); LC-MS: m/z=+455(M+H)+.

Example 125 Preparation of1-(3-[[1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl]-1H-1,3-benzodiazol-2-yl]oxy]azetidin-1-yl)ethan-1-one

Step 1—Synthesis of 1-(3-hydroxyazetidin-1-yl)ethan-1-one

To a solution of azetidin-3-ol (3.0 g, 27.40 mmol) and triethylamine(8.33 g, 82.48 mmol) in tetrahydrofuran (150 mL) was added acetylchloride (2.15 g, 27.39 mmol) dropwise with stirring at −78° C. over 10min. The resulting solution was stirred for 3 h at 20-30° C. The solidmaterial was removed by filtration. The filtrate was concentrated undervacuum and purified on a silica gel column (methanol/ethyl acetate(1/10)) to afford 500 mg (14%) of 1-(3-hydroxyazetidin-1-yl)ethan-1-oneas yellow oil. ¹H NMR (400 MHz, DMSO) delta 3.60 (t, J=4.8 Hz, 2H), 2.83(t, J=4.8 Hz, 2H), 2.21 (s, 3H).

Step 2—Synthesis of1-(3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidin-1-yl)ethan-1-one

A mixture of4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(500 mg, 1.23 mmol), 1-(3-hydroxyazetidin-1-yl)ethan-1-one (1 g, 8.69mmol) and potassium t-butoxide (500 mg, 5.21 mmol) inN,N-dimethylformamide (5 mL) kept under nitrogen in a 30-mL sealed tubewas stirred overnight at room temperature. The reaction mixture wasfiltered through a frit filter and the filtrate was purified on a C18column (acetonitrile/water, 5:95-80:20) to yield 160 mg (29%) of1-(3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidin-1-yl)ethan-1-oneas a yellow solid. LC-MS: m/z=+403 (M+H)+.

Step 3—Synthesis of1-(3-[[1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl]-1H-1,3-benzodiazol-2-yl]oxy]azetidin-1-yl)ethan-1-one

A mixture of1-(3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidin-1-yl)ethan-1-one(130 mg, 0.29 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (200 mg,1.32 mmol), bis(triphenylphosphine)palladium(II) dichloride (250 mg,0.36 mmol) and triethylamine (1 mL) in DMSO (2 mL) was stirred undernitrogen for 5 h at 70° C. The reaction mixture was cooled to roomtemperature then filtered through a frit filter. The filtrate waspurified by preparative HPLC to give 30 mg (21%) of1-(3-[[1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl]-1H-1,3-benzodiazol-2-yl]oxy]azetidin-1-yl)ethan-1-oneas a white solid: ¹H NMR (400 MHz, DMSO) delta 8.41 (d, J=5.6 Hz, 1H),8.19 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.29 (d, J=8.0 Hz, 1H), 7.11-7.07(m, 3H), 6.45 (s, 1H), 6.38 (s, 1H), 5.57 (t, J=3.6 Hz, 1H), 4.61 (t,J=8.0 Hz, 1H), 4.37-4.29 (m, 2H), 4.03 (t, J=5.2 Hz, 1H), 2.41 (s, 3H),1.81 (d, J=4.4 Hz, 6H); LC-MS: m/z=+474 (M+H)+.

Example 126 Preparation of 4-[1-(2-aminopyrimidin-4-yl)-2-(oxan-4-yloxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

Step 1—Synthesis of4-[6-bromo-2-(oxan-4-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine

Sodium hydride (200 mg, 5.00 mmol, 60% dispersion in mineral oil) wasadded in several portions into a solution of4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(500 mg, 1.23 mmol) and oxan-4-ol (1.00 g, 9.79 mmol) inN,N-dimethylformamide (10 mL) under an atmosphere of nitrogen. Thereaction mixture was stirred overnight at room temperature and thenfiltered through a frit filter. The filtrate was purified on a C18column (acetonitrile/water, 5:95-80:20) to give 170 mg (28%) of4-[6-bromo-2-(oxan-4-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine asa brown solid. LC-MS: m/z=+390 (M+H)+.

Step 2—Synthesis of 4-[1-(2-aminopyrimidin-4-yl)-2-(oxan-4-yloxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

A mixture of4-[6-bromo-2-(oxan-4-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(150 mg, 0.27 mmol, 70%), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (200mg, 1.32 mmol), bis(triphenylphosphine)palladium(II) dichloride (220 mg,0.31 mmol) and triethylamine (1 mL) in dimethylsulfoxide (2 mL) wasstirred under nitrogen atmosphere for 5 hr at 70° C. The reactionmixture was cooled to room temperature then filtered through a fritfilter to remove the catalyst. The filtrate was purified by preparativeHPLC to give 30 mg (24%) of4-[1-(2-aminopyrimidin-4-yl)-2-(oxan-4-yloxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-olas a white solid. ¹H NMR (400 MHz, DMSO) delta 8.41 (d, J=5.6 Hz, 1H),8.15 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.28-7.07 (m, 1H), 7.08 (s, 2H),6.99 (d, J=5.6 Hz, 1H), 6.46 (s, 1H), 6.37 (s, 1H), 5.39-5.35 (m, 1H),3.88-3.82 (m, 2H), 3.06-3.55 (m, 2H), 2.51 (s, 3H), 2.24-2.16 (m, 2H),1.88-1.82 (m, 5H); LC-MS: m/z=+461 (M+H)+.

Example 127 Preparation of3-[[1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl]-1H-1,3-benzodiazol-2-yl]oxy]propane-1,2-diol

Step 1—Synthesis of3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]propane-1,2-diol

A mixture of4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(500 mg, 1.23 mmol), cesium carbonate (3.2 g, 9.82 mmol) andpropane-1,2,3-triol (565 mg, 6.14 mmol) in N,N-dimethylformamide (3 mL)was stirred for 12 h at room temperature. The reaction mixture wasfiltered through a frit filter to remove any solid material and thefiltrate was purified by Flash-Preparative HPLC to give 90 mg (19%) of3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]propane-1,2-diolas a yellow solid. ¹H NMR (400 MHz, DMSO) delta 8.46 (s, 1H), 8.37 (d,J=5.2 Hz, 1H), 7.44-7.38 (m, 2H), 7.13-7.09 (m, 3H), 5.18 (d, J=5.2 Hz,1H), 4.80 (d, J=6.0 Hz, 1H), 4.68-4.64 (m, 1H), 4.52-4.48 (m, 1H), 3.93(d, J=4.8 Hz, 1H), 3.52-3.46 (m, 2H); LC-MS: m/z=+380 (M+H)+.

Step 2—Synthesis of3-[[1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl]-1H-1,3-benzodiazol-2-yl]oxy]propane-1,2-diol

A mixture of3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]propane-1,2-diol(80 mg, 0.21 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (160 mg,1.06 mol), bis(triphenylphosphine)palladium(II) dichloride (160 mg, 0.22mmol) and triethylamine (1 mL) in DMSO (2 mL) was stirred for 5 h at 70°C. under nitrogen atmosphere. The reaction mixture was cooled to roomtemperature and filtered through a frit filter. The filtrate waspurified by preparative HPLC to afford 23 mg (24%) of3-[[1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(5-methyl-1,2-oxazol-3-yl)but-1-yn-1-yl]-1H-1,3-benzodiazol-2-yl]oxy]propane-1,2-diolas a white solid. ¹H NMR (300 MHz, DMSO) delta 8.38 (d, J=5.4 Hz, 1H),8.20 (s, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 7.07-7.05(m, 3H), 6.46 (s, 1H), 6.38 (s, 1H), 5.19 (d, J=5.4 Hz, 1H), 4.83-4.80(m, 1H), 4.64 (d, J=3.6 Hz, 1H), 4.52 (d, J=6.3 Hz, 1H), 3.93 (d, J=4.5Hz, 1H), 3.52-3.49 (m, 3H), 2.40 (s, 3H), 1.82 (s, 3H); LC-MS: m/z=451(M+H)+.

Example 128 Preparation of4-[1-(2-aminopyrimidin-4-yl)-2-(2,2,2-trifluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol

A mixture of 4-[6-bromo-2-(2,2,2-trifluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (150 mg, 0.31 mmol,80% purity), 2-(pyrimidin-2-yl)but-3-yn-2-ol (300 mg, 2.02 mmol),bis(triphenylphosphine)palladium(II) dichloride (220 mg, 0.31 mmol) andtriethylamine (2 mL) in dimethylsulfoxide (3 mL) was stirred for 1.5 hrat 90° C. under nitrogen. The reaction mixture was cooled to roomtemperature then filtered through a frit filter to remove the catalyst.The filtrate was purified by preparative HPLC to afford 18 mg (13%) of4-[1-(2-aminopyrimidin-4-yl)-2-(2,2,2-trifluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl) but-3-yn-2-ol as alight brown solid: ¹H NMR (400 MHz, DMSO) delta 8.89 (d, J=4.8 Hz, 2H),8.44 (d, J=5.6 Hz, 1H), 8.12 (s, 1H), 7.51-7.48 (m, 2H), 7.28 (d, J=8.0Hz, 1H), 7.16 (s, 2H), 6.85 (d, J=5.2 Hz, 1H), 6.13 (s, 1H), 5.36-5.29(m, 2H), 1.89 (s, 3H); LC-MS: m/z=+456 (M+H)+.

Example 129 Preparation of4-[1-(2-aminopyrimidin-4-yl)-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

Step 1—Synthesis of4-[6-bromo-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine

A mixture of (2,2-dimethyl-1,3-dioxolan-4-yl)methanol (800 mg, 6.05mmol), cesium carbonate (1.7 g, 5.22 mmol) and4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(500 mg, 1.23 mmol) in N,N-dimethylformamide (4 mL) was stirred for 12hr at room temperature. The reaction mixture was quenched with 20 mL ofwater and the precipitate was collected by filtration. The solid wasdried in a vacuum oven to afford 385 mg (75%) of4-[6-bromo-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amineas a yellow solid. ¹H NMR (400 MHz, CDCl₃) delta 8.40 (d, J=5.2 Hz, 2H),7.40 (s, 2H), 7.21 (d, J=6.0 Hz, 1H), 5.28 (s, 2H), 4.77-4.60 (m, 3H),4.22-4.20 (m, 1H), 3.96-3.92 (m, 1H), 1.49 (s, 3H), 1.42 (s, 3H); LC-MS:m/z=+420 (M+H)+.

Step 2—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

A mixture of4-[6-bromo-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(150 mg, 0.32 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (300 mg,1.98 mmol), bis(triphenylphosphine)palladium(II) dichloride (300 mg,0.43 mmol) and triethylamine (2 mL) in dimethylsulfoxide (3 mL) wasstirred for 1 h at 70° C. under a nitrogen atmosphere. The reactionmixture was cooled to room temperature then filtered through a fritfilter to remove the catalyst. The filtrate was purified on a C18 column(acetonitrile/water, 5:95-80:20) to yield 27 mg (17%) of4-[1-(2-aminopyrimidin-4-yl)-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-olas a white solid: ¹H NMR (400 MHz, DMSO) delta 8.38 (d, J=5.2 Hz, 1H),8.18 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.09 (s,2H), 7.02 (d, J=5.2 Hz, 1H), 6.44 (s, 1H), 6.38 (s, 1H), 4.69-4.54 (m,3H), 4.11 (t, J=7.4 Hz, 1H), 3.89 (t, J=7.2 Hz, 1H), 2.41 (s, 3H), 1.81(s, 3H), 1.32 (d, J=16 Hz, 6H); LC-MS: m/z=+491 (M+H)+.

Example 130 Preparation of4-[1-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol

A mixture of2-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]ethan-1-ol(420 mg, 1.08 mmol), 2-(pyrimidin-2-yl)but-3-yn-2-ol (1 g, 6.75 mmol,6.25 equiv), bis(triphenylphosphine)palladium(II) dichloride (800 mg,1.14 mmol) and triethylamine (2 mL) in dimethylsulfoxide (3 mL) wasstirred under nitrogen for 1 hr at 90° C. The resulting mixture wasconcentrated under vacuum and the residue was purified by preparativeHPLC to yield 18 mg (4%) of4-[1-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-olas a light brown solid: ¹H NMR (400 MHz, D₂O) delta 8.75 (d, J=5.2 Hz,2H), 7.52 (d, J=5.6 Hz, 1H), 7.46 (t, J=5 Hz, 1H), 7.30 (s, 1H), 6.76(d, J=8.0 Hz, 1H), 6.55 (d, J=8.0 Hz, 1H), 6.24 (d, J=5.2 Hz, 1H), 3.90(s, 2H), 3.61 (s, 2H), 1.80 (s, 3H); LC-MS: m/z=+418 (M+H)+.

Example 131 Preparation of1-[2-[1-(2-aminopyrimidin-4-yl)-2-[(2-methoxyethyl)amino]-1H-1,3-benzodiazol-6-yl]ethynyl]cyclohexan-1-ol

Step 1—Synthesis of1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-1,3-benzodiazol-2-amine

A mixture of4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(1.5 g, 3.68 mmol) and cesium carbonate (2.5 g, 7.67 mmol) in2-methoxyethan-1-amine (15 mL) was stirred under nitrogen for 3 days atroom temperature. The reaction mixture was concentrated under vacuum andthe residue was purified on a C18 column (acetonitrile/water,5:95-80:20) to give 0.55 g (39%) of1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-1,3-benzodiazol-2-amineas a yellow solid. LC-MS: m/z=+363 (M+H)+.

Step 2—Synthesis of1-[2-[1-(2-aminopyrimidin-4-yl)-2-[(2-methoxyethyl)amino]-1H-1,3-benzodiazol-6-yl]ethynyl]cyclohexan-1-ol

A mixture of1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-1,3-benzodiazol-2-amine(150 mg, 0.39 mmol, 95%), triethylamine (2 mL), 1-ethynylcyclohexan-1-ol(300 mg, 2.42 mmol) and bis(triphenylphosphine)palladium(II) dichloride(300 mg, 0.43 mmol) in dimethylsulfoxide (3 mL) was stirred undernitrogen for 1 hr at 70° C. The reaction mixture was purified on a C18column (acetonitrile/water, 5:95-80:20) to give 30 mg (19%) of1-[2-[1-(2-aminopyrimidin-4-yl)-2-[(2-methoxyethyl)amino]-1H-1,3-benzodiazol-6-yl]ethynyl]cyclohexan-1-olas a white solid: ¹H NMR (300 MHz, DMSO) delta 8.43 (d, J=5.4 Hz, 1H),8.22 (d, J=5.4 Hz, 1H), 7.50 (s, 1H), 7.30-7.10 (m, 4H), 6.91 (s, 1H),5.33 (s, 1H), 4.69-4.55 (m, 4H), 3.30 (s, 3H), 1.90-1.20 (m, 10H);LC-MS: m/z=407 (M+H)+.

Example 132 Preparation of4-[1-(2-aminopyrimidin-4-yl)-2-[[1-(2-hydroxyethyl)azetidin-3-yl]oxy]-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

Step 1—Synthesis of tert-butyl3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidine-1-carboxylate

A mixture of4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(1 g, 2.45 mmol), tert-butyl 3-hydroxyazetidine-1-carboxylate (2 g,11.55 mmol) and cesium carbonate (4 g, 12.28 mmol) inN,N-dimethylformamide (15 mL) was stirred under nitrogen overnight atroom temperature. The resulting solution was quenched with 200 mL ofwater. The precipitate was collected by filtration, washed with 200 mLof water and dried in a vacuum oven to give 750 mg (60%) of tert-butyl3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidine-1-carboxylateas a yellow solid: LC-MS: m/z=+461 (M+H)+.

Step 2: Synthesis of4-[2-(azetidin-3-yloxy)-6-bromo-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine

Trifluoroacetic acid (0.5 mL) was added dropwise into a solution oftert-butyl3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidine-1-carboxylate(250 mg, 0.49 mmol, 90%) in dichloromethane (2 mL) at 0° C. The reactionmixture was stirred at room temperature for 2 hr. Triethylamine was thenadded to adjust the pH of the solution to 8. The mixture wasconcentrated under vacuum to give 2 g (88%) of4-[2-(azetidin-3-yloxy)-6-bromo-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amineas dark red oil: LC-MS: m/z=+361 (M+H)+.

Step 3: Synthesis of2-(3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidin-1-yl)ethan-1-ol

A mixture of4-[2-(azetidin-3-yloxy)-6-bromo-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(2 g, 0.44 mmol, 8% purity) and triethylamine (1.5 mL) in2-bromoethan-1-ol (1.5 mL) was stirred at room temperature for 12 h. Thereaction mixture was purified on a C18 column (water/acetonitrile,5:95-80:20) to yield 100 mg (50%) of2-(3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidin-1-yl)ethan-1-olas a yellow solid: LC-MS: m/z=+405 (M+H)+.

Step 4: Synthesis of4-[1-(2-aminopyrimidin-4-yl)-2-[[1-(2-hydroxyethyl)azetidin-3-yl]oxy]-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

A mixture of2-(3-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]azetidin-1-yl)ethan-1-ol(80 mg, 0.20 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (160 mg,1.06 mmol), bis(triphenylphosphine)palladium(II) dichloride (160 mg,0.23 mmol) and triethylamine (1 mL) in dimethylsulfoxide (2 mL) wasstirred under nitrogen for 2 hr at 70° C. The reaction mixture wascooled to room temperature then filtered through a frit filter to removethe catalyst. The filtrate was purified by preparative HPLC to give 7 mg(7%) of4-[1-(2-aminopyrimidin-4-yl)-2-[[1-(2-hydroxyethyl)azetidin-3-yl]oxy]-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-olas a white solid: ¹H NMR (400 MHz, DMSO) delta 8.41 (d, J=5.6 Hz, 1H),8.17 (s, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 1H), 7.10 (s,2H), 7.01 (d, J=5.6 Hz, 1H), 6.45 (s, 1H), 6.37 (s, 1H), 5.37 (t, J=5.2Hz, 1H), 4.44 (t, J=5.4 Hz, 1H), 3.75 (t, J=7.2 Hz, 2H), 3.41 (t, J=6.0Hz, 2H), 3.28 (t, J=6.8 Hz, 2H), 2.57 (s, 2H), 2.41 (s, 3H), 1.81 (s,3H); LC-MS: m/z=+476 (M+H)+.

Example 133 Preparation of4-[1-(2-aminopyrimidin-4-yl)-2-[(2-methoxyethyl)amino]-1H-1,3-benzodiazol-6-yl]-2-methylbut-3-yn-2-ol

A mixture of1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-1,3-benzodiazol-2-amine(120 mg, 0.33 mmol), 2-methylbut-3-yn-2-ol (277.2 mg, 3.30 mmol),bis(triphenylphosphine)palladium(II) dichloride (231.67 mg,) andtriethylamine (2.4 mL) in dimethylsulfoxide (1 mL) was stirred undernitrogen for 1 hr at 70° C. The reaction mixture was cooled to roomtemperature and the solid material was removed by filtration. Thefiltrate was diluted with 5 mL of water then extracted with 3×30 mL ofethyl acetate. The combined organic layers was dried over anhydroussodium sulfate and concentrated under vacuum. The residue was purifiedby preparative HPLC to give 5.0 mg (4%) of4-[1-(2-aminopyrimidin-4-yl)-2-[(2-methoxyethyl)amino]-1H-1,3-benzodiazol-6-yl]-2-methylbut-3-yn-2-olas a white solid: ¹H NMR (300 MHz, DMSO) delta 8.43 (d, J=5.4 Hz, 1H),8.21 (d, J=5.4 Hz, 1H), 7.47 (s, 1H), 7.25 (s, 1H), 7.16-7.12 (m, 3H),6.91 (d, 1H), 5.40 (s, 1H), 3.63-3.57 (m, 4H), 3.35 (s, 3H), 1.47 (s,6H); LC-MS: m/z=+367 (M+H)+.

Example 134 Preparation of4-[1-(2-aminopyrimidin-4-yl)-2-[(2-methoxyethyl)amino]-1H-1,3-benzodiazol-6-yl]-2-(4-methyl-1,3-thiazol-2-yl)but-3-yn-2-ol

A mixture of1-(2-aminopyrimidin-4-yl)-6-bromo-N-(2-methoxyethyl)-1H-1,3-benzodiazol-2-amine(150 mg, 0.37 mmol), 2-(4-methyl-1,3-thiazol-2-yl)but-3-yn-2-ol (137.6mg, 0.82 mmol), bis(triphenylphosphine)palladium(II) dichloride (150 mg,0.21 mmol) and triethylamine (0.7 mL) in dimethylsulfoxide (1 mL) undernitrogen in a 10-mL sealed tube was stirred for 1 hr at 70° C. Thereaction mixture was cooled to room temperature then purified on asilica gel column (dichloromethane/methanol, 8:1) to give 19.6 mg (11%)of4-[1-(2-aminopyrimidin-4-yl)-2-[(2-methoxyethyl)amino]-1H-1,3-benzodiazol-6-yl]-2-(4-methyl-1,3-thiazol-2-yl)but-3-yn-2-olas yellow oil: ¹H NMR (300 MHz, DMSO) delta 8.40 (d, J=5.4 Hz, 2H), 8.22(t, J=5.0 Hz 1H), 7.49 (s, 1H), 7.27 (d, J=8.1 Hz, 1H), 7.16 (t, J=10.5Hz, 2H), 6.91 (d, J=5.4 Hz, 1H), 6.89 (s, 1H), 6.86 (s, 1H), 3.62-3.59(m, 4H), 3.32 (d, J=12.3 Hz, 3H), 2.35 (s, 3H), 1.85 (s, 3H); LC-MS:m/z=+450 (M+H)+.

Example 135 Preparation of4-[1-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-fluoropyridin-2-yl)but-3-yn-2-ol

A mixture of2-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]ethan-1-ol(200 mg, 0.57 mmol), 2-(5-fluoropyridin-2-yl)but-3-yn-2-ol (940 mg, 5.69mmol), bis(triphenylphosphine)palladium(II) dichloride (200 mg, 0.28mmol) and triethylamine (0.5 mL) in dimethylsulfoxide (1 mL) wasirradiated with microwave radiation under nitrogen for 1 hr at 120° C.The reaction mixture was cooled to room temperature then filteredthrough a frit filter to remove the catalyst. The filtrate wasconcentrated under vacuum and the crude product (80 mg) was purified bypreparative HPLC to give 3.7 mg (1%) of4-[1-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-fluoropyridin-2-yl)but-3-yn-2-olas a light yellow solid: ¹H NMR (300 MHz, DMSO) delta 8.54 (d, J=2.7 Hz,1H), 8.37 (d, J=5.7 Hz, 1H), 8.15 (d, J=1.2, 1H), 7.84 (q, 1H),7.78-7.72 (m, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.24 (q, 1H), 7.10-7.04 (m,3H), 6.37 (s, 1H), 5.03 (s, 1H), 4.60 (t, J=4.5 Hz, 2H), 3.81 (d, J=4.5Hz, 2H), 1.82 (s, 3H); LC-MS: m/z=+435 (M+H)+.

Example 136 Preparation of(2R)-4-[1-(2-aminopyrimidin-4-yl)-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

Step 1—Synthesis of 4-[2-(2-fluoroethoxy)-6-iodo-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine

A solution of4-[6-iodo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(1 g, 2.20 mmol), 2-fluoroethane-1-ol (900 mg, 14.05 mmol) and cesiumcarbonate (4.3 g, 13.20 mmol) in N,N-dimethylformamide (10 mL) wasstirred for 14 hr at room temperature. The reaction mixture was dilutedwith 50 mL of ethyl acetate then washed with 5×10 mL of water. Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified on a silica gel column (ethylacetate/petroleum ether, 10:1) to afford 150 mg (17%) of4-[2-(2-fluoroethoxy)-6-iodo-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amineas brown oil: LC-MS: m/z=400 (M+H)+.

Step 2—Synthesis of (2R)-4-[1-(2-aminopyrimidin-4-yl)-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol

A solution of 4-[2-(2-fluoroethoxy)-6-iodo-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (130 mg, 0.33mmol), (2R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol (148 mg, 0.97mmol), bis(triphenylphosphine)palladium(II) dichloride (34 mg, 0.05mmol) in triethylamine (1 mL) and dimethylsulfoxide (1 mL) wasirradiated with microwave radiation under nitrogen in a 8-mL vial at 90°C. for 30 min. The resulting solution was cooled to room temperature anddiluted with 30 mL of ethyl acetate. The solid material was removed byfiltration. The residue was concentrated under vacuum then purified on asilica gel column (ethyl acetate/petroleum ether, 2:1) to give 10 mg(7%) of (2R)-4-[1-(2-aminopyrimidin-4-yl)-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-olas a light brown solid. ¹H NMR (400 MHz, MeOD) delta 8.47 (s, 1H), 8.35(d, J=5.6 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.39-7.36 (m, 1H), 7.15 (d,J=5.6 Hz, 1H), 4.95-4.90 (m, 2H), 4.85-4.81 (m, 2H), 2.63 (s, 3H), 1.96(s, 3H); LC-MS: m/z=+424 (M+H)+.

Example 137 Preparation of4-[1-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-chloropyridin-2-yl)but-3-yn-2-ol

A solution of2-[[1-(2-aminopyrimidin-4-yl)-6-bromo-1H-1,3-benzodiazol-2-yl]oxy]ethan-1-ol(200 mg, 0.57 mmol), 2-(5-chloropyridin-2-yl)but-3-yn-2-ol (518 mg, 2.85mmol), bis(triphenylphosphine)palladium(II) dichloride (400 mg, 0.57mmol) and triethylamine (0.5 mL) in DMSO (0.5 mL) was irradiated undernitrogen in a 10-mL sealed tube with microwave radiation for 2 h at 100°C. The reaction mixture was cooled to room temperature and the solidmaterial was removed by filtration. The filtrate was concentrated undervacuum and the crude product (50 mg) was purified by preparative HPLC togive 2 mg (1%) of4-[1-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)-1H-1,3-benzodiazol-6-yl]-2-(5-chloropyridin-2-yl)but-3-yn-2-olas a light yellow solid: ¹H NMR (400 MHz, DMSO) delta 8.61 (s, 1H), 8.38(d, J=5.6 Hz, 1H), 8.16 (s, 1H), 7.98-7.82 (m, 1H), 7.81 (d, J=8.4 Hz,1H), 7.43 (d, J=8.4 Hz, 1H), 7.26-7.24 (m, 1H), 7.06 (d, J=5.2 Hz, 3H),6.44 (s, 1H), 5.06 (t, J=5.6 Hz, 1H), 4.61 (t, J=4.8 Hz, 2H), 3.83-3.80(m, 2H), 1.82 (s, 3H); LC-MS: m/z=+451 (M+H)+.

Example 138 Preparation of4-[1-(2-aminopyrimidin-4-yl)-2-(oxetan-3-yloxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol

Step 1—Synthesis of 4-[2-(oxetan-3-yloxy)-6-[2-(trimethylsilyl)ethynyl]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine

To a solution of4-[6-bromo-2-(oxetan-3-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(900 mg, 2.48 mmol) in piperidine (7.3 mL) was introducedtetrakis(triphenylphosphine)palladium(0) (172 mg, 0.15 mmol), copper(I)iodide (28 mg, 0.15 mmol) and ethynyltrimethylsilane (0.88 mL, 6.21mmol). The reaction mixture was warmed to 65° C. for 5 hr. After coolingto RT, the reaction mixture was concentrated in vacuo, DCM (5 mL) wasadded and the solution re-evaporated to dryness in vacuo (re-evaporationprocess repeated twice). Purification of the residue by columnchromatography (Biotage, DCM containing a 3-8% gradient of methanol)furnished the title compound as a brown solid: LC-MS: m/z=+380.05(M+H)+.

Step 2 Synthesis of4-[6-ethynyl-2-(oxetan-3-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine

To a solution of4-[2-(oxetan-3-yloxy)-6-[2-(trimethylsilyl)ethynyl]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(450 mg, 1.19 mmol) in dry THF (5 mL) at RT was introduced TBAF (0.88 mLof a 1M solution in THF, 0.88 mmol). After 20 minutes, the reactionmixture was concentrated in vacuo, DCM (5 mL) added and the solutionre-evaporated to dryness in vacuo (re-evaporation process repeatedtwice). Purification of the residue by silica gel flash columnchromatography (eluent: DCM containing a 2-10% gradient of methanol)furnished the title compound as a yellow solid: ¹H (500 MHz, DMSO) delta4.83-4.70 (2H, m), 5.04-4.93 (2H, m), 5.85-5.77 (1H, m), 7.18-7.07 (3H,m), 7.33 (1H, dd, J=8.2, 1.5 Hz), 7.45 (1H, d, J=8.2 Hz), 8.36 (1H, s),8.40 (1H, d, J=5.5 Hz); LCMS: m/z=+307.95 (M+H)+.

Step 3—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-2-(oxetan-3-yloxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol

To a solution of4-[6-ethynyl-2-(oxetan-3-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(270 mg, 0.88 mmol) in dry THF (5 mL) at −78° C. was introduced lithiumdiisopropylamide (1.10 mL of a 2M solution in THF, 2.20 mmol). After 15minutes, 1-pyrimidin-2-yl-ethanone (107 mg, 0.88 mmol) was added and thereaction mixture maintained at −78° C. for 15 minutes. Following 2 hr atRT, saturated aqueous ammonium chloride (0.5 ml) was added and thesolution concentrated in vacuo. The residue was dissolved in DCM (10mL), washed with water (2 mL), dried (Na₂SO₄), filtered and concentratedin vacuo. Purification of the residue by column chromatography (Biotage,DCM containing a 0-12% gradient of methanol) furnished the titlecompound as a yellow solid: ¹H NMR (500 MHz, DMSO) delta 1.90 (3H, s),4.78 (2H, dd, J=7.8, 4.9 Hz), 4.98 (2H, t, J=7.1 Hz), 5.87-5.80 (1H, m),6.16 (1H, s), 7.11 (1H, d, J=5.5 Hz), 7.14 (2H, s), 7.25 (1H, dd, J=8.2,1.2 Hz), 7.45 (1H, d, J=8.2 Hz), 7.52 (1H, t, J=4.8 Hz), 8.16 (1H, s),8.44 (1H, d, J=5.5 Hz), 8.91 (2H, d, J=4.8 Hz); LC-MS: m/z=+430.05(M+H)+.

Example 139 Preparation of 4-[1-(2-aminopyrimidin-4-yl)-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol

Step 1—Synthesis of4-[6-bromo-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine

A solution of4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(500 mg, 1.23 mmol), 2-fluoroethan-1-ol (236 mg, 3.68 mmol) and cesiumcarbonate (1.2 g, 3.68 mmol) in N,N-dimethylformamide (3 mL) was stirredin a 20-mL sealed tube under nitrogen overnight at room temperature. Thereaction mixture was diluted with 30 mL of water and the precipitate wascollected by filtration to give 340 mg (79%) of4-[6-bromo-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amineas a yellow solid; LC-MS: m/z=+352 (M+H)+.

Step 2: Synthesis of 4-[2-(2-fluoroethoxy)-6-[2-(trimethylsilyl)ethynyl]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine

A solution of4-[6-bromo-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(150 mg, 0.43 mmol), ethynyltrimethylsilane (126 mg, 1.28 mmol),bis(triphenylphosphine) palladium(II) dichloride (120 mg, 0.17 mmol) andtriethylamine (0.5 mL) in dimethylsulfoxide (1 mL) was irradiated withmicrowave radiation under nitrogen in a sealed tube at 80° C. for 40min. The reaction mixture was diluted with 10 mL of dichloromethane andthe solid material was removed by filtration. The filtrate wasconcentrated under vacuum and the residue was purified on a silica gelcolumn (ethyl acetate/petroleum ether, 3:1) to give 60 mg (38%) of4-[2-(2-fluoroethoxy)-6-[2-(trimethylsilyl)ethynyl]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amineas a yellow solid: LC-MS: m/z=+370 (M+H)+.

Step 3: Synthesis of4-[6-ethynyl-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine

A solution of 4-[2-(2-fluoroethoxy)-6-[2-(trimethylsilyl)ethynyl]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(100 mg, 0.27 mmol) and potassium fluoride (64 mg, 0.68 mmol) inmethanol (3 mL) was stirred at 50° C. for 3 hr. The reaction mixture wasconcentrated under vacuum and the residue was diluted with 30 mL ofethyl acetate. The resulting mixture was washed with 3×10 mL of waterand the organic layer was dried over anhydrous sodium sulfate andconcentrated under vacuum to give 70 mg (87%) of4-[6-ethynyl-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amineas a yellow solid: LC-MS: m/z=+298 (M+H)+.

Step 4: Synthesis of 4-[1-(2-aminopyrimidin-4-yl)-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol

To a solution of4-[6-ethynyl-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(30 mg, 0.10 mmol) in tetrahydrofuran (0.5 mL) under a nitrogenatmosphere at −78° C. was added a lithium diisopropylamide solution (0.3mL, 3.00 equiv) dropwise with stirring. The reaction mixture was stirredat −78° C. for 15 min. A solution of 1-(pyrimidin-2-yl)ethan-1-one (48.8mg, 0.40 mmol) in tetrahydrofuran (0.5 mL) was then added and themixture was stirred at −78° C. for another 20 min. The resultingsolution was then stirred at room temperature for 13 h. The reaction wasthen quenched by the addition of saturated ammonium chloride solution (1mL) and the mixture was extracted with 10 mL of ethyl acetate. Theorganic layer was dried over anhydrous sodium sulfate and concentratedunder vacuum. The residue was purified on a silica gel column (ethylacetate/petroleum ether, 1:3) to give 3.7 mg (9%) of4-[1-(2-aminopyrimidin-4-yl)-2-(2-fluoroethoxy)-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol as anoff-white solid: ¹H NMR (400 MHz, DMSO) delta 8.89 (d, J=4.8 Hz, 2H),8.40 (d, J=5.6 Hz, 1H), 8.13 (d, J=1.2 Hz, 1H), 7.51-7.44 (m, 2H),7.25-7.22 (m, 1H), 7.10 (s, 1H), 6.96 (d, J=5.2 Hz, 1H), 6.12 (s, 1H),4.93-4.88 (m, 2H), 4.80 (s, 2H), 1.88 (s, 3H); LC-MS: m/z=+420 (M+H)+.

Example 140 Preparation of4-[1-(2-aminopyrimidin-4-yl)-2-[(pyrrolidin-1-yl)carbonyl]-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

Step 1—Synthesis of4-[6-bromo-2-[(pyrrolidin-1-yl)carbonyl]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine

A mixture of4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(500 mg, 1.23 mmol), pyrrolidine (1 mL) and cesium carbonate (2 g, 6.14mmol) in N,N-dimethylformamide (5 mL) was stirred for 24 h at roomtemperature. The reaction mixture was purified on a C18 column(acetonitrile/water, 5:95-80:20) to give 240 mg (51%) of4-[6-bromo-2-[(pyrrolidin-1-yl)carbonyl]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amineas a white solid: ¹H NMR (300 MHz, DMSO) delta 8.42 (d, J=5.1 Hz, 1H),8.11 (d, J=1.8 Hz, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.57-7.53 (m, 1H), 7.07(s, 2H), 6.71 (d, J=5.4 Hz, 1H), 3.60 (d, J=6.3 Hz, 2H), 3.50 (t, J=6.6Hz, 2H), 1.92 (s, 4H); LC-MS: m/z=+387 (M+H)+.

Step 2—Synthesis of4-[1-(2-aminopyrimidin-4-yl)-2-[(pyrrolidin-1-yl)carbonyl]-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

A mixture of4-[6-bromo-2-[(pyrrolidin-1-yl)carbonyl]-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine(200 mg, 0.49 mmol), 2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (200 mg,1.32 mmol), bis(triphenylphosphine)palladium(II) dichloride (350 mg,0.50 mmol) and triethylamine (2 mL) in dimethylsulfoxide (3 mL) wasstirred under nitrogen at 70° C. for 2 hr. The reaction mixture wascooled to room temperature and purified on a C18 column(acetonitrile/water, 5:95-80:20) to afford 88 mg (38%) of4-[1-(2-aminopyrimidin-4-yl)-2-[(pyrrolidin-1-yl)carbonyl]-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-olas a light yellow solid. ¹H NMR (300 MHz, DMSO) delta 8.42 (d, J=5.1 Hz,1H), 7.86 (s, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.41 (d, J=8.7 Hz, 1H), 7.03(s, 2H), 6.74 (d, J=5.1 Hz, 1H), 6.50 (s, 1H), 6.36 (s, 1H), 3.61 (d,J=6.6 Hz, 2H), 3.48 (d, J=6.6 Hz, 2H), 2.40 (s, 3H), 1.92 (s, 4H), 1.80(s, 3H); LC-MS: m/z=+458 (M+H)+.

Example 141

Preparation(2R)-4-[1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

Step 1—Synthesis of4-(6-bromo-2-methyl-1,3-benzodiazol-1-yl)-1,3,5-triazin-2-amine

To a solution of 2-N-(2-amino-5-bromophenyl)-1,3,5-triazine-2,4-diamine(2.50 g, 8.89 mmol) in methanol (25 mL) and THF (100 mL) was addedtrimethyl orthoacetate (16.77 ml, 133.4 mmol) and TsOH (153.14 mg, 0.89mmol). The reaction mixture was stirred at 70° C. for 1 hr then allowedto cool to RT overnight. Saturated aqueous sodium bicarbonate (30 mL)was introduced and the resulting precipitous solution filtered. Thefiltrate was extracted into DCM (3×100 mL extractions). The combinedorganic extracts were washed with brine (30 mL), dried (Na₂SO₄),filtered and concentrated in vacuo. The orange/yellow solid residue wasthen triturated from a mixture of DCM and MeOH to give the titlecompound as a pale yellow powder (400 mg): ¹H NMR (500 MHz, DMSO) delta2.89 (3H, s), 7.46 (1H, dd, J=8.5, 1.9 Hz), 7.57 (1H, d, J=8.4 Hz), 8.02(1H, s), 8.10 (1H, s), 8.61 (1H, d, J=1.8 Hz), 8.64 (1H, s); LC-MS:m/z=+306.7 (M+H)+.

Step 2—Synthesis of(2R)-4-[1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol

To a solution of4-(6-bromo-2-methyl-1,3-benzodiazol-1-yl)-1,3,5-triazin-2-amine (160 mg,0.52 mmol) in piperidine (2 mL) was introducedtetrakis(triphenylphosphine)palladium(0) (60.59 mg, 0.05 mmol),copper(I) iodide (9.99 mg, 0.05 mmol) and(2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol (118.9 mg, 0.79 mmol).The reaction was then warmed to 95° C. for 40 minutes (75 W, microwaveheating). The reaction mixture was then cooled to RT and concentrated invacuo. Purification of the residue by flash column chromatography (4-8%MeOH gradient in DCM) gave the title compound as a pale brown solid (77mg): ¹H NMR (500 MHz, DMSO) delta 1.81 (3H, s), 2.41 (3H, s), 2.90 (3H,s), 6.37 (1H, s), 6.51 (1H, s), 7.33 (1H, dd, J=8.28, 1.50 Hz), 7.60(1H, d, J=8.20 Hz), 8.01 (1H, br. s.), 8.06 (1H, br. s.), 8.40 (1H, s),8.66 (1H, s); LC-MS: m/z=+376.45 (M+H)+.

Example 142 Preparation of(2R)-4-[1-(4-amino-1,3,5-triazin-2-yl)-2-cyclopropyl-1H-1,3-benzodiazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

Step 1—Synthesis of4-(6-bromo-2-cyclopropyl-1,3-benzodiazol-1-yl)-1,3,5-triazin-2-amine

To a solution of 2-N-(2-amino-5-bromophenyl)-1,3,5-triazine-2,4-diamine(6 g, 21.34 mmol) in DMF (60 mL) was added cyclopropanecarbaldehyde(2.07 ml, 27.75 mmol) followed by oxone (7.83 g, 12.81 mmol). Thereaction mixture was stirred at RT for 24 hr. The reaction mixture wasthen cooled to 0° C. and saturated aqueous sodium bicarbonateintroduced. A brown precipitate was removed by vacuum filtration. Thesolid was washed with DCM (100 ml). The organic phase of the filtratewas separated and the aqueous phase extracted with DCM (2×100 mLextractions). The combined organics were washed with brine and thendried (Na₂SO₄), filtered and concentrated in vacuo to furnish the crudetitle compound as a brown solid: ¹H NMR (500 MHz, DMSO) delta 1.32-1.02(4H, m), 7.41 (1H, dd, J=8.5, 1.9 Hz), 7.50 (1H, d, J=8.5), 8.05 (1H,s), 8.11 (1H, s), 8.49 (1H, d, J=1.8 Hz), 8.66 (1H, s); LC-MS:m/z=+330.90 (M+H)+. This compound of 85% purity LC-MS (UV) was usedwithout further purification.

Step 2—Synthesis of(2R)-4-[1-(4-amino-1,3,5-triazin-2-yl)-2-cyclopropyl-1H-1,3-benzodiazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

To a microwave vessel was added4-(6-bromo-2-cyclopropyl-1,3-benzodiazol-1-yl)-1,3,5-triazin-2-amine(0.3 g, 0.91 mmol) followed by piperidine (2.5 mL),tetrakis(triphenylphosphine)palladium(0) (104.68 mg, 0.09 mmol),copper(I) iodide (17.25 mg, 0.09 mmol) and(2R)-2-(1,3-thiazol-2-yl)but-3-yn-2-ol (0.28 g, 1.81 mmol). The reactionwas capped and stirred in the microwave at 95° C. for 25 minutes (55 W).The reaction mixture was cooled to RT and concentrated in vacuo. Theresidue was re-dissolved in EtOAc and re-evaporated in vacuo (twice).The crude residue was subjected to column chromatography (Biotage, 0-8%methanol gradient in DCM) and the partially purified product trituratedwith a mixture of EtOAc/heptane to give the title compound as a beigesolid: ¹H NMR (DMSO, 500 MHz) delta 1.06-1.20 (4H, m), 1.89 (3H, s),3.24-3.29 (1H, m), 7.04 (1H, s), 7.30 (1H, dd, J=8.2, 1.4 Hz), 7.53 (1H,d, J=8.2 Hz), 7.69 (1H, d, J=3.2 Hz), 7.78 (1H, d, J=3.2 Hz), 8.05 (1H,s), 8.09 (1H, s), 8.29 (1H, s), 8.68 (1H, s); LC-MS: m/z=+400 (M+H)+.

Example 143

Examples in Table 15 were prepared by procedure described in Example142-b by reacting4-(6-bromo-2-methyl-1,3-benzodiazol-1-yl)-1,3,5-triazin-2-amine or4-(6-bromo-2-cyclopropyl-1,3-benzodiazol-1-yl)-1,3,5-triazin-2-aminewith the appropriate but-3-yn-2-ol in Step 2.

TABLE 15 LC-MS No Structure Name ¹H NMR (M + H) T15-143.1

4-[1-(4-amino-1,3,5- triazin-2-yl)-2-methyl- 1H-1,3-benzodiazol-6-yl]-2-(1,3-thiazol-2- yl)but-3-yn-2-ol (500 MHz, DMSO) delta 1.90 (3H,s), 2.90 (3H, s), 7.33 (1H, dd, J = 8.28, 1.50 Hz), 7.60 (1H, d, J =8.20 Hz), 7.69 (1H, d, J = 3.15 Hz), 7.78 (1H, d, J = 3.31 Hz),7.95-8.02 (1H, m), 8.03-8.09 (1H, m), 8.34-8.43 (1H, m), 8.66 (1H, s)378   T15-143.2

4-[1-(4-amino-1,3,5- triazin-2-yl)-2-cyclopropyl-1H-1,3-benzodiazol-6-yl]- 2-(5-methyl-1,2-oxazol-3- yl)but-3-yn-2-ol(500 MHz, DMSO) delta 1.08-1.21 (4H, m), 1.81 (3H, s), 2.41 (3H, s),6.35-6.38 (1H, m), 6.50 (1H, s), 7.31 (1H, dd, J = 8.20, 1.58 Hz), 7.54(1H, d, J = 8.35 Hz), 8.04 (1H, s), 8.08 (1H, s), 8.28- 8.31 (1H, m),8.67- 8.70 (1H, m) 402   T15-143.3

4-[1-(4-amino-1,3,5- triazin-2-yl)-2-methyl-1H- 1,3-benzodiazol-6-yl]-2-(5-methyl-1,2-oxazol- 3-yl)but-3-yn-2-ol (500 MHz, MeOD) delta 1.91(3H, s), 2.48 (3H, s), 3.00 (3H, s), 6.34 (1H, s), 7.44 (1H, d, J = 9.46Hz), 7.58 (1H, d, J = 8.20 Hz), 8.49-8.76 (2H, m) 376   T15-143.4

(2R)-4-[1-(4-amino-1,3,5- triazin-2-yl)-2-methyl-1H-1,3-benzodiazol-6-yl]- 2-(1,3-thiazol-2- yl)but-3-yn-2-ol (500 MHz,DMSO) delta 1.90 (3H, s), 2.90 (3H, s), 7.05 (1H, s), 7.33 (1H, dd, J =8.2, 1.5 Hz), 7.60 (1H, d, J = 8.2 Hz), 7.69 (1H, d, J = 3.2 Hz), 7.78(1H, d, J = 3.2 Hz), 8.16-7.94 (2H, m), 8.40 (1H, s), 8.66 (1H, s).378.4 T15-143.5

4-[1-(4-amino-1,3,5- triazin-2-yl)-2-methyl-1H- 1,3-benzodiazol-6-yl]-1-cyclopropyl-2-methylbut- 3-yn-2-ol (500 MHz, MeOD) delta 0.13-0.31 (2H,m), 0.48-0.64 (2H, m), 0.92-1.10 (1H, m), 1.54-1.68 (4H, m), 1.79 (1H,dd, J = 13.64, 6.38 Hz), 2.97 (3H, s), 4.59 (1H, br. s.), 7.37 (1H, dd,J = 8.35, 1.26 Hz), 7.53 (1H, d, J = 8.20 Hz), 8.52 (1H, s), 8.59 (1H,s) 349.1

Example 144 Preparation of2-((1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)ethynyl)bicyclo[2.2.1]heptan-2-ol

A mixture of4-(6-bromo-2-methyl-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-amine (200mg, 0.66 mmol) and 2-ethynylbicyclo[2.2.1]heptan-2-ol (85 mg, 1.3 mmol)in DMF (2.5 mL) was treated with palladium(II) acetate (16 mg, 0.07mmol), DPPP (58 mg, 0.14 mmol), copper(I) iodide (5 mg, 0.04 mmol) andpotassium carbonate (180 mg, 1.3 mmol), then the mixture was heated at120° C. for 40 min under microwave irradiation. After cooling to RT, thereaction mixture was filtered and the filtrate concentrated in vacuo.Purification of the residue by silica gel column chromatographyfurnished the title compound (18.5 mg, yield 8%): ¹H NMR: (400 MHz,MeOD) delta 1.30-1.47 (m, 4H), 1.56-1.67 (m, 1H), 1.92-2.48 (m, 5H),2.97 (s, 3H), 7.36 (dd, J=1.6, 8.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 8.50(s, 1H), 8.60 (s, 1H); LC-MS: m/z=+361.0 (M+H)⁺.

Example 145 Preparation of3-((1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)ethynyl)tetrahydro-2H-pyran-3-ol

The title compound was prepared by the procedure described for2-((1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)ethynyl)bicyclo[2.2.1]heptan-2-ol, by substituting 2-ethynylbicyclo [2.2.1]heptan-2-ol(1-b) with 3-ethynyltetrahydro-2H-pyran-3-ol. The title product,3-((1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)ethynyl)tetrahydro-2H-pyran-3-olwas purified by silica gel chromatography: ¹H NMR (400 MHz, DMSO) delta1.66-1.78 (m, 4H), 1.97-2.05 (m, 1H), 3.01 (s, 3H), 3.36-3.71 (m, 4H),7.47 (dd, J=1.6, 8.4 Hz, 1H), 7.71 (dd, J=0.4, 8.4 Hz, 1H), 8.17 (s,1H), 8.24 (s, 1H), 8.48 (dd, J=0.4, 1.6 Hz, 1H), 8.71 (s, 1H); LC-MS:m/z=+350.9 (M+H)⁺.

Example 146 Preparation of3-((1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)ethynyl)oxetan-3-ol

The title compound was prepared by procedure described for Example 144,by substituting 2-ethynyl-bicyclo[2.2.1]heptan-2-ol (1-b) with3-ethynyloxetan-3-ol (3-a). The title product,3-((1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)ethynyl)oxetan-3-olwas purified by reverse phase preparative HPLC (37.5 mg, yield 35%): ¹HNMR (400 MHz, DMSO) delta 2.88 (s, 3H), 4.60 (d, J=6.8 Hz, 2H), 4.78 (d,J=6.8 Hz, 2H), 6.59 (s, 1H), 7.37 (dd, J=1.6, 8.0 Hz, 1H), 7.60 (dd,J=0.4, 8.4 Hz, 1H), 7.99 (s, 1H), 8.04 (s, 1H), 8.47 (dd, J=0.8, 1.6 Hz,1H), 8.62 (s, 1H); LC-MS: m/z=+323.0 (M+H)⁺.

Example 147 Preparation of3-((1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)ethynyl)-3-hydroxycyclobutanecarbonitrite

The title compound was prepared by procedure described for Example 144,by substituting 2-ethynylbicyclo [2.2.1]heptan-2-ol (1-b) with3-ethynyl-3-hydroxycyclobutanecarbonitrile. The product was purified bySFC chromatography (yield 6.2%) to give the title product: ¹H NMR (400MHz, MeOD) delta 2.62-2.67 (m, 2H), 2.94-3.00 (m, 5H), 3.17-3.25 (m,1H), 7.44 (d, J=8.4 Hz), 7.58 (d, J=8.4 Hz), 8.61-8.62 (m, 2H). LCMS:m/z=+346.1 (M+H)⁺.

Example 148 Preparation of4-(1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-2-methyl-1-(1H-pyrazol-1-yl)but-3-yn-2-ol

The title compound was prepared by the procedure described in Example144, by substituting 2-ethynylbicyclo [2.2.1]heptan-2-ol (1-b) with2-methyl-1-(1H-pyrazol-1-yl)but-3-yn-2-ol in Step 3. The residue waspurified by Prep-HPLC to get4-(1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-2-methyl-1-(1H-pyrazol-1-yl)but-3-yn-2-ol (12.2 mg, yield 5%). ¹H NMR (400 MHz, MeOD) delta 1.51 (s,3H), 3.09 (s, 3H), 4.42 (s, 2H), 6.36 (s, 1H), 7.46-7.80 (m, 4H), 8.63(dd, J=0.4, 1.6 Hz, 1H), 8.66 (s, 1H). LCMS: m/z=+374.9 (M+H)+.

Example 149 Preparation of4-[1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-1,3-benzodiazol-6-yl]-2-(pyrazin-2-yl)but-3-yn-2-ol

Step 1—Synthesis of4-{2-methyl-6-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazol-1-yl}-1,3,5-triazin-2-amine

To a mixture of4-(6-bromo-2-methyl-1,3-benzodiazol-1-yl)-1,3,5-triazin-2-amine (250 mg,0.74 mmol), tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.06 mmol),copper(I) iodide (11 mg, 0.06 mmol) and ethynyl(trimethyl)silane 0.230ml, 1.51 mmol) was added triethylamine (2.6 mL). The mixture was purgedwith nitrogen for 2 minutes and was stirred at 80° C. for 15 min in themicrowave. LC-MS shows 50% conversion. The mixture was retreated withanother equivalent of tetrakis(triphenylphosphine)palladium (70 mg)copper(I) iodide (11 mg) and ethynyl(trimethyl)silane (0.230 ml).Heating in the microwave at 90° C. was continued for another 30 mins.Purification by Biotage column chromatography (DCM to 5% MeOH/DCM togive the title compound; LC-MS: m/z+323.40 (M+H)+.

Step 2—Synthesis of4-(6-ethynyl-2-methyl-1,3-benzodiazol-1-yl)-1,3,5-triazin-2-amine

To a solution of4-{2-methyl-6-[2-(trimethylsilyl)ethynyl]-1,3-benzodiazol-1-yl}-1,3,5-triazin-2-amine(90 mg, 0.279 mmol) in THF (1 mL) was added 1M TBAF in THF (0.33 mL,0.33 mmol). The mixture was allowed to stand at RT for 1 hr, the mixturewas concentrated in vacuo and purified by column chromatography (Biotage5-8% MeOH/DCM) to give the title compound; LC-MS: m/z+250.95 (M+H)+.

Step 3—Synthesis of4-[1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-1,3-benzodiazol-6-yl]-2-(pyrazin-2-yl)but-3-yn-2-ol

To a solution of4-(6-ethynyl-2-methyl-1,3-benzodiazol-1-yl)-1,3,5-triazin-2-amine (80mg, 0.29 mmol) in THF (0.5 mL) at −78° C. under N₂ (g) was added 2M LDAin THF (0.43 mL, 0.86 mmol). After 5 min 1-pyrazin-2-yl-ethanone (105mg, 0.86 mmol) in THF (0.5 mL) was added. After 20 min, the mixture wasallowed to warm to RT and was stirred for 1 hr. The reaction mixture wasquenched by addition of sat aq NH₄Cl (0.5 mL). The volatiles wereremoved by evaporation under reduced pressure. The mixture was dilutedwith EtOAc (10 ml) and washed with water (2 mL), dried (Na₂SO₄),filtered and concentrated in vacuo. Purification by Biotagechromatography (100% DCM to 8% MeOH/DCM) gave the title compound (15 mg,14% yield); ¹H NMR (250 MHz, DMSO) delta 1.86 (3H, s), 2.89 (3H, s),6.63 (1H, s), 7.32 (1H, dd, J=8.22, 1.52 Hz), 7.58 (1H, d, J=8.22 Hz),7.96 (1H, s), 7.98 (1H, s), 8.39 (1H, d, J=1.22 Hz), 8.59-8.63 (1H, m),8.63-8.67 (2H, m), 9.02 (1H, d, J=1.37 Hz); LC-MS: m/z+373.4 (M+H)+.

Example 150 Preparation of4-[1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-1,3-benzodiazol-6-yl]-2-(pyrimidin-2-yl)but-3-yn-2-ol

The title compound was prepared by procedure described for Example149-c, by replacing 1-pyrazin-2-yl-ethanone with1-(pyrimidin-2-yl)ethanone in Step 3; ¹H NMR (500 MHz, DMSO) delta 1.88(3H, s), 2.89 (3H, s), 6.06-6.35 (1H, m), 7.29 (1H, dd, J=8.28, 1.50Hz), 7.50 (1H, t, J=4.89 Hz), 7.57 (1H, d, J=8.20 Hz), 8.01 (1H, s),8.07 (1H, s), 8.37 (1H, d, J=0.95 Hz), 8.65 (1H, s), 8.89 (2H, d, J=4.73Hz); LC-MS: m/z+373.4 (M+H)+.

Example 151 Preparation of1-[3-(4-Amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-ylethynyl]-3-hydroxymethyl-cyclobutanol(151-b1) and3-{3-[3-(4-Amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-yl]-1-hydroxy-prop-2-ynyl}-cyclobutanol(151-62)

Step 1—Synthesis of1-[3-(4-amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-ylethynyl]-3-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutanoland3-[3-(4-amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-yl]-1-[3-(tert-butyl-dimethyl-silanyloxy)-cyclobutyl]-prop-2-yn-1-ol

To a solution of the crude product from Example 36-d (0.24 g, 1.0 mmol)in N,N-dimethyl-formamide (3 mL) was added1,3-bis(diphenylphosphino)propane (40 mg, 0.1 mmol), Pd(OAc)₂ (10 mg,0.05 mmol), K₂CO₃ (207 mg, 1.5 mmol),4-(6-bromo-2-methyl-benzoimidazol-1-yl)-[1,3,5]triazin-2-ylamine (150mg, 1 mmol) and CuI (5 mg, 0.025 mmol). Then the solution was bubbledwith N₂ for 5 min and microwaved for 1 h at 120° C. under nitrogen. Thereaction mixture was filtrated and the filtrate was purified by columnto afford1-[3-(4-amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-ylethynyl]-3-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutanol(55 mg, 24%) and3-[3-(4-amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-yl]-1-[3-(tert-butyl-dimethyl-silanyloxy)-cyclobutyl]-prop-2-yn-1-ol(50 mg, 22%): LCMS m/z=+465.1 (M+H)+.

Step 2—Synthesis of1-[3-(4-amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-ylethynyl]-3-hydroxymethyl-cyclobutanol(151-b1)

In a solution of1-[3-(4-amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-ylethynyl]-3-(tert-butyl-dimethyl-silanyloxymethyl)-cyclobutanol(55 mg, 0.1 mmol) in tetrahydrofuran (20 ml) was addedtetrabutylammonium fluoride (70 mg, 0.3 mmol). Then the solution stirredovernight at room temperature. The reaction mixture was washed withwater and purified by column to afford title compound (30 mg, 86%): ¹HNMR (400 MHz, MeOD) delta 2.05-2.10 (m, 2H), 2.36-2.38 (m, 1H),2.57-2.62 (m, 2H), 3.59 (d, J=6.4 Hz, 2H), 7.40 (dd, J=1.6, 8.0 Hz, 1H),7.55 (dd, J=0.4, 8.4 Hz, 1H), 8.56 (dd, J=0.4, 1.6 Hz, 1H), 8.59 (s,1H). LCMS: m/z=+351.1 (M+H)+.

Synthesis of 13-{3-[3-(4-amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-yl]-1-hydroxy-prop-2-ynyl}-cyclobutanol(151-b2)

In a solution of3-[3-(4-amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-yl]-1-[3-(tert-butyl-dimethyl-silanyloxy)-cyclobutyl]-prop-2-yn-1-ol(50 mg, 0.1 mmol) in tetrahydrofuran (20 ml) was addedtetrabutylammonium fluoride (70 mg, 0.3 mmol). Then the solution stirredovernight at room temperature. The reaction mixture was washed withwater and purified by column to afford title compound (20 mg, 57%): ¹HNMR (400 MHz, MeOD) delta 1.80-2.20 (m, 3H), 2.32-2.43 (m, 2H), 2.94 (s,3H), 3.56-3.70 (m, 0.5H), 4.05-4.17 (m, 0.5H), 4.45-4.48 (m, 0.5H),7.35-7.51 (m, 2H), 8.53-8.57 (m, 2H). LCMS: m/z=+350.9 (M+H)+.

Example 152 Preparation of4-[3-(4-amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-yl]-2,2-dimethyl-but-3-yn-1-ol

Step 1—Synthesis of4-{6-[4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-1-ynyl]-2-methyl-benzoimidazol-1-yl}-[1,3,5]triazin-2-ylamine

In a solution of4-(6-bromo-2-methyl-benzoimidazol-1-yl)-[1,3,5]triazin-2-ylamine (0.15g, 0.5 mmol) in N,N-dimethyl-formamide (3 ml) were added1,3-bis(diphenylphosphino)propane (40 mg, 0.1 mmol), Pd(OAc)₂ (10 mg,0.05 mmol), K₂CO₃ (207 mg, 1.5 mmol),tert-butyl-(2,2-dimethyl-but-3-ynyloxy)-dimethyl-silane (150 mg, 1 mmol)and CuI (5 mg, 0.025 mmol). Then the solution bubbled N₂ for 5 min andwas microwaved for 1 h at 120° C. under nitrogen. The reaction mixturewas filtrated and the filtrate was purified by column to afford4-{6-[4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-1-ynyl]2-methyl-benzoimidazol-1-yl}-[1,3,5]triazin-2-ylamine(140 mg, 66%): LCMS m/z=+437.0 (M+H)+.

Step 2—Synthesis of4-[3-(4-amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-yl]-2,2-dimethyl-but-3-yn-1-ol

In a solution of4-{6-[4-(tert-butyl-dimethyl-silanyloxy)-3,3-dimethyl-but-1-ynyl]2-methyl-benzoimidazol-1-yl}-[1,3,5]triazin-2-ylamine(140 mg, 0.32 mmol) in THF (10 ml) was added tetrabutyl-ammoniumfluoride (170 mg, 0.64 mmol). Then the solution stirred overnight atroom temperature. The reaction mixture was washed with water andpurified by column to afford the title compound4-[3-(4-amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-yl]-2,2-dimethyl-but-3-yn-1-ol(5-e) (30 mg, 29%): ¹H NMR (400 MHz, DMSO) delta 1.23 (s, 6H), 2.89 (s,3H), 3.39 (d, J=6.0 Hz, 2H), 5.00 (t, J=5.6 Hz, 2H), 7.29 (dd, J=1.6,8.4 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 7.99 (s, 1H), 8.02 (s, 1H), 8.33(t, J=0.4 Hz, 1H), 8.65 (s, 1H). LCMS m/z=+323.1 (M+H)+.

Example 153 Preparation of{1-[3-(4-amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-ylethynyl]-cyclopentyl}-methanol(6-f)

Step 1—Synthesis of4-{6-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclopentylethynyl]-2-methyl-benzoimidazol-1-yl}-[1,3,5]triazin-2-ylamine

The title compound was prepared by procedure described in Example 144,by substituting 2-ethynylbicyclo [2.2.1]heptan-2-ol (1-b) withtert-butyl-(1-ethynyl-cyclopentylmethoxy)-dimethyl-silane.4-(6-bromo-2-methyl-benzoimidazol-1-yl)-[1,3,5]triazin-2-ylamine (200mg, 0.66 mmol), tert-butyl-(1-ethynyl-cyclopentylmethoxy)-dimethylsilane(313 mg, 1.3 mmol), Pd(OAc)₂ (29 mg, 0.13 mmol), CuI (25 mg, 0.13 mmol),DPPP (102 mg, 0.26 mmol) and K₂CO₃ (181 mg, 1.31 mmol) were combined ina flask, and DMF (10 mL) was added. The resulting mixture was stirred at120° C. for 3 h under N₂. The reaction mixture was filtered via silicagel, the filtrate was concentrated, and the residue was washed withEtOAc and MeOH to afford the desired product (80 mg, 26%). LCMS:m/z=+463.1 (M+H)⁺.

Step 2—Synthesis of{1-[3-(4-amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-ylethynyl]-cyclopentyl}-methanol

4-{6-[1-(tert-butyl-dimethyl-silanyloxymethyl)-cyclopentylethynyl]-2-methyl-benzoimidazol-1-yl}-[1,3,5]triazin-2-ylamine(6-e) (80 mg, 0.17 mmol) was dissolved in THF (100 mL), TBAF (113 mg,0.43 mmol) was added. The resulting mixture was stirred at roomtemperature for 12 h. Water (5 mL) was added, extracted with EtOAc. Theorganic phase was concentrated, purified via prep-TLC separation toafford the title target (27.5 mg, 47%): ¹H NMR (400 MHz, DMSO) delta1.55-1.76 (m, 8H), 2.86 (s, 3H), 3.40 (d, J=4.8 Hz, 2H), 4.96 (t, J=4.8Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.90-8.10 (m,2H), 8.30 (t, J=0.8 Hz, 1H), 8.63 (s, 1H). LCMS: m/z=+349.1 (M+H)⁺.

Example 154 Preparation of4-[3-(4-amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-yl]-2-methyl-but-3-yne-1,2-diol

Step 1—Synthesis of4-[3-(4-amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-yl]-1-(tert-butyl-dimethyl-silanyloxy)-2-methyl-but-3-yn-2-ol

The title compound was prepared by procedure described in Example 144,by substituting 2-ethynylbicyclo [2.2.1]heptan-2-ol with1-(tert-butyl-dimethyl-silanyloxy)-2-methyl-but-3-yn-2-ol. A mixture of4-(6-bromo-2-methyl-benzoimidazol-1-yl)-[1,3,5]triazin-2-ylamine (300mg, 0.98 mmol),1-(tert-butyl-dimethyl-silanyloxy)-2-methyl-but-3-yn-2-ol (380 mg, 1.9mmol) in DMF (2.5 mL) was treated with Pd(OAc)₂ (20 mg, 0.1 mmol), dppp(60 mg, 0.2 mmol), CuI (5 mg, 0.05 mmol) and K₂CO₃ (280 mg, 2.0 mmol),then the mixture was heated at 120° C. for 40 min under microwave. Afterfiltrated and concentrated by vacuum, the residue was purified by silicagel chromatography (DCM: MeOH=20:1) to get the title compound4-[3-(4-amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-yl]-1-(tert-butyl-dimethyl-silanyloxy)-2-methyl-but-3-yn-2-ol(7-b) (300 mg, yield 68%).

Step 2—Synthesis of4-[3-(4-amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-yl]-1-(tert-butyl-dimethyl-silanyloxy)-2-methyl-but-3-yn-2-ol

To a solution of4-[3-(4-amino-[1,3,5]triazin-2-yl)-2-methyl-3H-benzoimidazol-5-yl]-1-(tert-butyl-dimethyl-silanyloxy)-2-methyl-but-3-yn-2-ol(300 mg, 0.68 mmol) in THF (20 mL) was added TBAF (dissolved in 5 mLTHF) at 0° C. for about 1 h. After washing with water and extractingwith EtOAc, the crude product was obtained and further purified byPrep-TLC (DCM: MeOH=10:1) to get the title compound (22.8 mg, yield10%): ¹H NMR (400 MHz, MeOD) delta 1.54 (s, 3H), 2.98 (s, 3H), 3.61 (s,2H), 7.43 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.0 Hz, 1H), 8.60 (s, 2H). LCMS:m/z=+325.1 (M+H)+.

Example 155 Preparation of(2R)-4-[1-(4-amino-1,3,5-triazin-2-yl)-2-(methoxymethyl)-1H-1,3-benzodiazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

Step 1 Synthesis of4-[6-bromo-2-(methoxymethyl)-1H-1,3-benzodiazol-1-yl]-1,3,5-triazin-2-amine

To a solution of 2-N-(2-amino-5-bromophenyl)-1,3,5-triazine-2,4-diamine(1.00 g, 3.56 mmol) in DMF (5 mL) was introduced methoxyacetic acid (320mg, 3.56 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (750 mg, 3.91 mmol), 1-hydroxy-7-azabenzotriazole (533 mg,3.91 mmol) and triethylamine (720 mg, 7.11 mmol). The reaction mixturewas stirred for 18 hr at RT and concentrated in vacuo. The residue wassuspended in water (100 mL) and the resulting precipitate collected byfiltration. After washing the filter cake with EtOAc (10 mL) andmethanol (10 mL), the crude amide was dried on the filter. Theintermediate amide was dissolved in glacial acetic acid (20 mL) andwarmed to 140° C. for 15 minutes (microwave heating in 4 batches ofequal volume). Following concentration of the reaction mixture in vacuo,toluene (20 mL) was introduced and the suspension concentrated in vacuo(repeated twice) to furnish the crude title compound as a brown oil:LC-MS: m/z=+334.90/336.75 (M+H)+. This compound, with LC-MS purity=86%UV, was used in the next step without further purification.

Step 2 Synthesis of(2R)-4-[1-(4-amino-1,3,5-triazin-2-yl)-2-(methoxymethyl)-1H-1,3-benzodiazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

To a solution of4-[6-bromo-2-(methoxymethyl)-1H-1,3-benzodiazol-1-yl]-1,3,5-triazin-2-amine(150 mg at 86% purity, 0.38 mmol) in piperidine (3 mL) was introducedtetrakis(triphenylphosphine)palladium(0) (22.2 mg, 0.02 mmol), copper(I)iodide (7.3 mg, 0.04 mmol) and (2R)-2-(1,3-thiazol-2-yl)but-3-yn-2-ol(118 mg, 0.77 mmol). The reaction was warmed to 70° C. for 1 hr. Aftercooling to RT, additional tetrakis(triphenylphosphine)palladium(0) (22.2mg, 0.02 mmol) was introduced and the reaction mixture warmed to 70° C.for a further 1 hr. The reaction mixture was concentrated in vacuo andthe residue purified by silica gel flash chromatography (DCM containinga 0-3% gradient of methanol) to furnish the title compound as a brownoil: ¹H NMR (500 MHz, DMSO) delta 1.90 (3H, s), 5.10 (2H, s), 7.06 (1H,br. s.), 7.31-7.40 (1H, m), 7.64-7.73 (2H, m), 7.75-7.80 (1H, m), 8.02(1H, br. s.), 8.08 (1H, br. s.), 8.30 (1H, s), 8.40-8.45 (1H, m), 8.65(1H, s); LC-MS: m/z=+408.00 (M+H)+.

Example 156 Preparation of4-[3-(2-aminopyrimidin-4-yl)-6-fluoro-1,3-benzodiazol-5-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

Step 1—Synthesis ofN-(5-bromo-4-fluoro-2-nitrophenyl)-2-chloropyrimidin-4-amine

To a solution of 2-chloropyrimidin-4-amine (1.31 g, 10.08 mmol) in THF(55 mL) at 0° C. was added sodium hydride (60% in oil, 806.69 mg, 20.17mmol) portion-wise. The reaction mixture was stirred at 0° C. to RT for10 minutes and 1-bromo-2,5-difluoro-4-nitrobenzene (1.2 g, 5.04 mmol)was added. The reaction mixture was stirred at 65° C. for 1 h. Thereaction mixture was cooled to RT and water (30 mL) was added. Productextracted into DCM (2×30 mL) and washed with water (20 mL). The combinedorganics were dried (Na₂SO₄), filtered and concentrated in vacuo. Thecrude product was purified by column chromatography (Biotage) elutedwith DCM:MeOH gradient (99:1 to 95:05) to afford the title compound asan orange solid (1005 mg, 56% yield); ¹H NMR (250 MHz, DMSO) delta 6.87(1H, d, J=5.83 Hz), 8.08 (1H, d, J=6.31 Hz), 8.18 (1H, d, J=8.35 Hz),8.27 (1H, d, J=5.83 Hz), 10.32 (1H, br. s.); LC-MS: m/z+348.70 (M+H)+.

Step 2—Synthesis of4-N-(5-bromo-4-fluoro-2-nitrophenyl)pyrimidine-2,4-diamine

To a solution ofN-(5-bromo-4-fluoro-2-nitrophenyl)-2-chloropyrimidin-4-amine (1.05 g,3.02 mmol) in 2-propanol (12 mL) in a pressure vessel was added ammoniumhydroxide (12 mL, 303 mmol) carefully at RT. The reaction vessel wassealed and stirred at 90° C. for 15 hr (4 bar). Extra aqueous ammonium(4 mL, 100 mmol) was added and the reaction heated at 90° C. for 1 hrthen cooled to 0° C. The resultant orange precipitate was filtered anddried by suction filtration to afford the title compound as an orangesolid (713 mg, 63% yield); ¹H NMR (500 MHz, DMSO) delta 9.55 (s, 1H),8.44 (d, J=6.6 Hz, 1H), 8.17 (d, J=8.6 Hz, 1H), 7.98 (d, J=5.6 Hz, 1H),6.31 (s, 2H), 6.19 (d, J=5.6 Hz, 1H); LC-MS: m/z+329.80 (M+H)+.

Step 3—Synthesis of4-N-(2-amino-5-bromo-4-fluorophenyl)pyrimidine-2,4-diamine

To a solution of4-N-(5-bromo-4-fluoro-2-nitrophenyl)pyrimidine-2,4-diamine (713 mg, 2.17mmol) in ethanol (30 mL) was added tin(II) chloride dihydrate (1.72 g,7.61 mmol) The reaction mixture was stirred at 60° C. for 1 hr. Uponcompletion, reaction mixture was evaporated to dryness and added to icewater (20 mL). The pH was adjusted to pH10 using sat Na₂CO₃ solution (30mL) and EtOAc (30 mL) was added. Saturated Rochelle's salt (20 mL) wasadded and the mixture stirred until separate layers were observed. Theorganic layer was separated and the aqueous layer extracted with EtOAc(2×5 mL). Combined organics were washed with saturated Rochelles salt(15 mL) followed by brine solution (15 mL) and dried over Na₂SO₄,filtered and concentrated in vacuo to afford the title compound as apale orange solid (500 mg, 68.7% yield); ¹H NMR (250 MHz, DMSO) delta8.11 (s, 1H), 7.75 (d, J=5.7 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 6.67 (d,J=11.1 Hz, 1H), 6.08 (s, 2H), 5.75 (d, J=5.7 Hz, 1H), 5.37 (s, 2H);LC-MS: m/z+299.75 (M+H)+.

Step 4—Synthesis of4-(6-Bromo-5-fluoro-benzoimidazol-1-yl)-pyrimidin-2-ylamine

To a solution of4-N-(2-amino-5-bromo-4-fluorophenyl)pyrimidine-2,4-diamine (500 mg, 1.68mmol) in methanol (6 mL) and THF (20 mL) was added trimethylorthoformate (5.59 ml, 50.32 mmol) and TsOH (0.03 ml, 0.17 mmol). Thereaction mixture was stirred at 70° C. for 1.5 hr. Reaction had onlyprogressed 6% by LC-MS. Extra trimethyl orthoformate (6 mL, 54.23 mmol)was added and stirred at 70° C. for 1 hr. Reaction mixture was cooledand sat NaHCO₃ (10 mL) was added. The product was extracted with DCM(3×10 mL) and the organics were washed with brine and then dried(Na₂SO₄), filtered and concentrated in vacuo to obtain title compound asa beige solid (500 mg, 63.8% yield); ¹H NMR (500 MHz, DMSO) delta 9.17(s, 1H), 8.97 (d, J=6.7 Hz, 1H), 8.37 (d, J=5.5 Hz, 1H), 7.81 (d, J=9.1Hz, 1H), 7.20 (s, 2H), 7.14 (d, J=5.6 Hz, 1H); LC-MS: m/z=+309.75(M+H)+.

Step 5—Synthesis of4-[3-(2-aminopyrimidin-4-yl)-6-fluoro-1,3-benzodiazol-5-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

To a pressure tube was added4-(6-Bromo-5-fluoro-benzoimidazol-1-yl)-pyrimidin-2-ylamine (66%, 250mg, 0.54 mmol), piperidine (1.5 mL),tetrakis(triphenylphosphine)palladium (61.9 mg, 0.05 mmol), copper(I)iodide (10.2 mg, 0.05 mmol) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol(164.09 mg, 1.07 mmol), degassed with N₂ for 5 min and stirred at 75° C.for 3 hr before concentrating in vacuo. The crude product was purifiedby column chromatography (Biotage) eluted with DCM: methanol gradient(98:2 to 90:10). The product obtained was triturated with methanol toobtain the title compound as an off-white solid (35 mg, 17.1% yield). ¹HNMR (500 MHz, DMSO) delta 1.94 (3H, s), 7.08 (1H, s), 7.13 (1H, d,J=5.36 Hz), 7.18 (2H, br. s.), 7.65-7.73 (2H, m), 7.78 (1H, d, J=3.15Hz), 8.39 (1H, br. s.), 8.64 (1H, d, J=6.46 Hz), 9.17 (1H, s); LC-MS:m/z+381.40 (M+H)+.

Example 156 Preparation of4-[3-(2-aminopyrimidin-4-yl)-6-fluoro-1,3-benzodiazol-5-yl]-2-methylbut-3-yn-2-ol

To a pressure tube was added3-(2-aminopyrimidin-4-yl)-7-bromo-6-fluoro-1,3 benzodiazol-4-amine (66%,250 mg, 0.54 mmol), piperidine (1.5 mL),tetrakis(triphenylphosphine)palladium (61.9 mg, 0.05 mmol), copper(I)iodide (10.2 mg, 0.05 mmol) and 2-methylbut-3-yn-2-ol (0.1 ml, 1.07mmol). The reaction was stirred at 75° C. for 2.5 h before concentratingin vacuo. The crude product was purified by column chromatography(Biotage) eluted with DCM: methanol gradient (98:3 to 90:10). Materialobtained triturated with methanol to obtain the title compound as anoff-white solid. (45 mg, 26.7% yield); ¹H NMR (500 MHz, DMSO) delta 1.52(6H, s), 5.53 (1H, s), 7.14 (1H, d, J=5.20 Hz), 7.18 (2H, br. s.), 7.67(1H, d, J=9.62 Hz), 8.40 (1H, br. s.), 8.63 (1H, d, J=6.62 Hz), 9.16(1H, s); LC-MS m/z+312.5 (M+H)+.

Example 157 Preparation of4-[1-(4-aminopyrimidin-2-yl)-1H-1,3-benzodiazol-6-yl]-2-(1,3-thiazol-2-yl)but-3-yn-2-ol

To a pressure tube was added2-(6-bromo-1,3-benzodiazol-1-yl)pyrimidin-4-amine (300 mg, 1.03 mmol),piperidine (2 mL), tetrakis(triphenylphosphine)palladium (119.5 mg, 0.10mmol), copper(I) iodide (19.7 mg, 0.10 mmol) and2-(1,3-thiazol-2-yl)but-3-yn-2-ol (316.84 mg, 2.07 mmol). The reactionwas stirred at 75° C. for 18 h. The reaction mixture was cooled beforeconcentrating in vacuo. The crude product was purified by columnchromatography (Biotage) eluted with DCM: methanol gradient (97:3 to90:1). Material obtained was triturated with methanol to afford thetitle compound as a beige solid. (43 mg, 11.5% yield); ¹H NMR (250 MHz,DMSO) delta 1.91 (3H, s), 6.41 (1H, d, J=5.79 Hz), 7.06 (1H, s), 7.37(1H, d, J=1.52 Hz), 7.45 (2H, br. s.), 7.65-7.84 (3H, m), 8.19 (1H, d,J=5.79 Hz), 8.62 (1H, d, J=1.07 Hz), 9.00 (1H, s); LC-MS m/z+3.

Example 158 Preparation of4-[1-[2-amino-5-(1-methylpyrazol-4-yl)pyrimidin-4-yl]indazol-6-yl]-2-methyl-but-3-yn-2-ol(158-b) Synthesis of5-bromo-4-(6-bromo-1H-indazol-1-yl)pyrimidin-2-amine

To a solution of 6-bromo-1H-indazole (1.01 eq) in DMF (50 mL) at 0° C.was added sodium hydride in oil (1.3 eq). The ice bath was removed after10 minutes and the reaction mixture was stirred for 30 minutes beforethe addition of 5-bromo-4-chloro-pyrimidin-2-amine (5.2 g). The reactionwas judged to be complete by LC-MS after heating overnight at 50° C. Thecrude reaction mixture was subsequently concentrated to drynesswhereupon the product was triterated from by sonication from Methanol toafford 7 g of 5-bromo-4-(6-bromo-1H-indazol-1-yl)pyrimidin-2-amine(158-a) as a light orange solid. ¹H NMR (400 MHz, DMSO-d6) δ 8.48 (s,1H), 8.41 (d, J=1.3 Hz, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.49 (dd, J=8.5,1.6 Hz, 1H), 7.30 (s, 2H).

Synthesis of4-[1-(2-amino-5-bromo-pyrimidin-4-yl)indazol-6-yl]-2-methyl-but-3-yn-2-ol(158-b)

5-bromo-4-(6-bromoindazol-1-yl)pyrimidin-2-amine (3 g) was reacted with2-methyl-3-butyn-2-ol (1 eq) via General Procedure Sonagashira Coupling(See, Chinchilla, R.; Najera, C. (2007), “The Sonogashira Reaction: ABooming Methodology in Synthetic Organic Chemistry”, Chem. Rev. 107:874-922) to afford 0.7 g of4-[1-(2-amino-5-bromo-pyrimidin-4-yl)indazol-6-yl]-2-methyl-but-3-yn-2-olfollowing flash column chromatography.4-[1-(2-amino-5-bromo-pyrimidin-4-yl)indazol-6-yl]-2-methyl-but-3-yn-2-ol(0.1 g) was reacted with 1-methyl-4-pyrazoleboronic acid pinacol estervia General Procedure Suzuki Coupling to afford 12.2 mg of4-[1-[2-amino-5-(1-methylpyrazol-4-yl)pyrimidin-4-yl]indazol-6-yl]-2-methyl-but-3-yn-2-olfollowing reverse phase hplc purification. MS (Q1) 374. ¹H NMR (400 MHz,DMSO-d6) δ 8.57 (s, 1H), 8.30 (s, 1H), 7.88-7.81 (m, 2H), 7.48 (s, 1H),7.24 (dd, J=8.3, 1.1 Hz, 1H), 7.05 (s, 2H), 6.98 (s, 1H), 5.47 (s, 1H),3.73 (s, 3H), 1.48 (s, 6H).

Example 159 Preparation of4-[1-[2-amino-5-(1-methylpyrazol-4-yl)pyrimidin-4-yl]indazol-6-yl]-2-methyl-but-3-yn-2-ol(159-a)

4-[1-(2-amino-5-bromo-pyrimidin-4-yl)indazol-6-yl]-2-methyl-but-3-yn-2-ol(0.075 g) was reacted 1-Boc-4-pyrazoleboronic acid pinacol ester viaGeneral Procedure Suzuki Coupling to afford 9.5 mg of4-[1-[2-amino-5-(1-methylpyrazol-4-yl)pyrimidin-4-yl]indazol-6-yl]-2-methyl-but-3-yn-2-olfollowing reverse phase hplc purification. MS (Q1) 360. ¹H NMR (400 MHz,DMSO-d6) δ12.71 (s, 1H), 8.62 (s, 1H), 8.30 (s, 1H), 7.84 (d, J=8.3 Hz,1H), 7.76 (s, 1H), 7.46 (s, 1H), 7.23 (d, J=8.2 Hz, 1H), 7.02 (s, 2H),5.45 (s, 1H), 1.47 (s, 6H).

Example 160

NIK Enzyme Inhibition Assay: The ability of the nuclear factor-kappa B(NF-kB)-inducing kinase (NIK) to catalyze the hydrolysis ofadenosine-5′-triphosphate (ATP) was monitored using the Transcreener ADP(adenosine-5′-diphosphate) assay (BellBrook Labs). Purified NIK (0.2-1nM) derived from a baculovirus-infected insect cell expression systemwas incubated with test compounds for 1-3.5 hours in 50 mM2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid buffer (pH 7.2)containing 10 mM MgCl₂, 2 mM dithiothreitol, 10 uM ATP, 0.01% TritonX-100, 0.1% gamma-globulins from bovine blood, 1% dimethylsulfoxide(DMSO), 12 ug/mL ADP antibody and 4 nM ADP-AlexaFluor® 633 tracer.Reactions were quenched by the addition of 20 mM2,2′,2″,2′″-(ethane-1,2-diyldinitrilo)tetraacetic acid and 0.01% Brij35. The tracer bound to the antibody was displaced by the ADP generatedduring the NIK reaction, which causes a decrease in fluorescencepolarization that was measured by laser excitation at 633 nm with aFluorescence Correlation Spectroscopy Plus reader (Evotec AG).Equilibrium dissociation constant (K_(i)) values for NIK inhibitors arecalculated from plots of activity vs inhibitor concentration usingMorrison's quadratic equation that accounts for the potential of tightbinding, and by also applying the conversion factor that accounted forcompetitive inhibition and the concentration of substrate used in theassay relative to its Michaelis constant (K_(m)). The compounds inlisted in Table 1 have the corresponding inhibitory value (Ki inmicromolar) for NIK (values for compounds are presented in the sameorder as found in Table 1): na, na, na, na, na, 0.00014, 0.00028, 0.411,0.0459, 0.0143, 0.559, 0.0093, 0.000262, 0.0069, 0.00032, 0.027, 2.9,0.0017, 0.19, 0.049, 0.0003, 0.0001, >5, 2.1, 0.012, 0.061, 0.57,0.00042, 0.0009, 0.060, 4.6, 0.0013, 0.023, 0.0921, 0.018, 0.85, 0.0023,0.016, 0.00025, 0.003, 0.0085, 0.00014, 0.0002, 0.0435, 0.000045,0.00016 and 0.00011, 0.013, 0.847, 0.152, 0.575, 0.01, 0.0004, 0.105,0.0002, 0.0016, 0.002, 0.00015, 0.00049, 0.0022, 0.383, 0.017, 0.00023,0.005, 0.00265, 0.00127, 0.004, 0.0027, 5 and 0.0005. The compounds inlisted in Table 1.1 have the corresponding inhibitory value (Ki inmicromolar) for NIK (values for compounds are presented in the sameorder as found in Table 1.1): 0.0001, 0.0002, 0.0002, 0.00022, 0.00032,0.00032, 0.0004, 0.0005, 0.0005, 0.0005, 0.0005, 0.0006, 0.0006, 0.0008,0.001, 0.001, 0.001, 0.001, 0.001, 0.001, 0.001, 0.001, 0.001, 0.001,0.001, 0.001, 0.002, 0.002, 0.002, 0.002, 0.002, 0.002, 0.002, 0.002,0.002, 0.002, 0.002, 0.002, 0.002, 0.002, 0.002, 0.003, 0.003, 0.003,0.003, 0.003, 0.003, 0.003, 0.004, 0.004, 0.004, 0.004, 0.004, 0.004,0.004, 0.004, 0.005, 0.005 0.005, 0.006, 0.006, 0.006, 0.006, 0.006,0.007, 0.007, 0.008, 0.009, 0.009, 0.009, 0.010, 0.012, 0.012, 0.013,0.014, 0.016, 0.020, 0.020, 0.022, 0.024, 0.025, 0.025, 0.027, 0.027,0.031, 0.039, 0.046, 0.052, 0.054, 0.069, 0.070, 0.078, 0.085, 0.087,0.100, 0.102, 0.111, 0.129, 0.13, 0.15, 0.31, 0.315, 0.342, 0.491,0.775, 0.913, 1.6, 1.6, 1.7, 1.7, 1.8, 2.4, 2.6, 3.9, 5, 5, 5, 5, 5, 5,0.0003, 5, na, 0.001, 5, na, 4.9, na, 5, 0.009, 0.841, 0.0004, 0.002,0.004, 0.002, 0.007, 0.0002, 0.020, 0.00528, 0.0002, 0.007, 0.002,0.003, 0.011, 3.4, 0.004, 0.0001 and 0.0003.

Example 161

Cellular Assay: Several assays were developed to profile the cellularactivities of NIK inhibitors.

(1) The first assay was used to profile whether a test compound caninhibit the NF-kB signally through NIK inhibition without affecting cellviability. In this assay, human embryonic kidney 293 cells was stablytransfected with a tetracycline-inducible NIK DNA construct containing acytomegalovirus promoter plus two reporter DNA constructs. One reporterencoded firefly luciferase under the control of three repeats of anNF-kB response element from the ELAM-1 gene and reflects the level ofNIK activity in the cells, whereas the other reporter constitutivelyexpressed Renilla luciferase under the control of the herpes simplexvirus thymidine kinase promoter and served as a general measure of cellviability. Cells were incubated with different concentrations ofcompounds (0.2% DMSO final) in medium containing 1 ug/mL doxycycline and10% tet-system approved fetal bovine serum (Clontech) for 24 hours,after which the reporters' signals were detected using the Dual Gloluciferase detection system (Promega) according to the vendor'sprotocol. The compounds listed in Table 1 have the correspondinginhibitory value (IC₅₀ in micromolar) for 293-NIK NF-kB-Luciferaseactivity (values for compounds are presented in the same order as foundin Table 1): na, 0.059, na, na, na, 0.105, 0.027, na, 20, 1.2, na, 1.8,0.0231, 0.879, 0.0361, 0.582, na, 0.142, na, 0.403, 0.059, 0.0331, na,na, 0.0573, 1.5, na, na, 0.0722, na, na, 0.589, 12.7, 3.7, 14.9, na,0.707, 1, 0.0311, 0.332, 0.309, 0.0142, 0.051, 2.8, 0.129, na, na, 1.5,na, na, na, 1.3, 0.062, 20, 0.31, 0.104, 0.091, 0.037, 0.085, 0.279, na,0.305, 0.064, 0.332, 0.133, 0.168, 0.217, 0.553, na and na.

The compounds in listed in Table 1 have the corresponding inhibitoryvalue (IC₅₀ in micromolar) for 293-NIK TK Renilla Luciferase activity:(values for compounds are presented in the same order as found in Table1): 6.4, 3.6, 20, na, 1.6, 9.3, 18.5, na, na, 2.6, na, na, na, na, na,na, na, na, na, na, na, na, na, na, na, na, na, na, na, na, na, na, na,na, na, na, na, na, na, na, na, na, na, na, na, na, na, >20, na, na, na,20, >20, 17, 1.3, 15.6, 0.967, 2.7, 11.2, 5.1, na, 20, 20, 20, 20, 20,17.6, 20, na and na.

(2) A second set of cell assay was used to define the selectivity of NIKinhibitors toward inhibition of classical vs. non-classical NF-kBsignaling and rely on quantification of the nuclear translocation of p52(NF-kB2) and REL-A (p65) using high content cellular imaging. For thep52 (non-classical NF-kB signaling) nuclear translocation assay, HeLacells were treated with different concentrations of compounds (0.2% DMSOfinal) in medium containing 10% fetal bovine serum and then stimulatedwith 100 ng/mL of an anti-lymphotoxin beta receptor antibody (R&DSystems) for 5 hours. In the REL-A nuclear translocation assay, HeLacells were incubated with compounds (0.2% DMSO final) for 4.5 hours inmedium containing 10% fetal bovine serum before stimulating them with 10ng/mL tumor necrosis factor (TNF)-α (R&D Systems) for 30 minutes. Cellswere fixed with 4% paraformaldehyde, permeabilized by adding 0.1% TritonX-100 in phosphate buffered saline, and then incubated with either 2ug/mL anti-p52 antibody (Millipore) or 400 ng/mL anti-REL-A (p65)antibody (Santa Cruz Biotechnology). Finally, the cells were incubatedwith an Alexa488-labeled secondary antibody (Invitrogen) and DRAQ5 DNAstain (Biostatus). Imaging was carried out using an Opera reader (PerkinElmer) and data are analyzed with the aid of Acapella software (PerkinElmer). The p52 or REL-A translocation into the nucleus was quantifiedby the ratio of the nuclear to cytoplasmic signal intensity. Theconcentration of inhibitor required for 50% inhibition (IC₅₀ values) inthese cell assays were derived from the plots of signal vs. inhibitorconcentration. The compounds in listed in Table 1 have the correspondinginhibitory value (IC₅₀ in micromolar) for NIK p52 Translocation Assay(values for compounds are presented in the same order as found in Table1, and “na” means the data for this assay is to be determined): 0.326,0.33, na, na, na, 0.218, 0.07, na, na, na, 0.129, 7.6, 0.077, 3.4, na,0.518, na, 0.059, 0.514, 0.127, na, na, 0.010, na, na, 0.313, 0.275, na,0.0727, na, na, na, na, na, na, 0.194, na, 6.4, 0.22, 0.346, na, na, naand na, na, na, na, na, na, 0.447, na, 0.089, 0.479, 0.489, 0.243,0.747, 1, na, 1.9, 0.552, 2.1, na. na, na, na, na and na.

The compounds in listed in Table 1 has the corresponding inhibitoryvalue (IC₅₀ in micromolar) for NIK RelA Translocation Assay (values forcompounds are presented in the same order as found in Table 1): 0.326,0.33, na, na, na, 0.218, 0.07, na, na, na, na, na, 0.129, 7.6, 0.077,3.4, na, 0.518, na, 0.059, 0.514, 0.127, na, na, 0.010, na, na, 0.313,0.275, na, na, 0.0727, na, na, na, na, na, na, 0.194, na, 6.4, 0.22,0.346, na, na, na, na, na, na, na, na, na, 0.447, na, 0.089, 0.479,0.489, 0.243, 0.747, 1, na, 1.9, 0.552, 2.1, na, na, na, na, na and na.

Example 162

Comparative data: PCT Application (WO 2009/158011) to Amgen, Inc.describes certain alkynyl alcohol formula as NIK inhibitors. Compoundsof the invention of Formula I, in which “A” group in Formula I is asdisclosed herein exhibit unexpectedly, superior properties in the assaysdescribed hereinabove as compared to compounds described in WO2009/158011 (See Table 16A-16D):

TABLE 16A 4-(1-(2-aminopyrimidin- 4-yl)indolin-6-yl)-2-4-(1-(2-aminopyrimidin-4- (thiazol-2-yl)but-3-yl)-1H-benzo[d]imidazol-6- Assay yn-2-ol yl)-2-(thiazol-2-yl)but-(micromolar) (WO2009/158011) 3-yn-2-ol NIK ADP (Ki) 0.0027 0.0003293-NIK 0.126 0.027 NF-kB-Luciferase (IC₅₀) 293-NIK TK 3.9 4.9 RenillaLuciferase (IC₅₀) NIK p52 0.862 0.070 Translocation (IC₅₀) NIKRelA >20 >20 Translocation (IC₅₀)

TABLE 16B 1-(2-aminopyrimidin-4- 4-(1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3- yl)-3-methyl-1H-indazol-6- (thiazol-2-yl)but-1-Assay yl)-2-(thiazol-2-yl)but-3- ynyl)-1H- (micromolar) yn-2-olbenzo[d]imidazol-2( NIK ADP (Ki) 0.0001 0.0003 293-NIK 0.011 0.59NF-kB-Luciferase (IC₅₀) 293-NIK TK 1.2 5.2 Renilla Luciferase (IC₅₀) NIKp52 0.222 0.514 Translocation (IC₅₀) NIK RelA >20 >20 Translocation(IC₅₀)

TABLE 16C 4-(1-(2-aminopyrimidin- 4-(1-(2-aminopyrimidin-4-yl)-1H-benzo[d]imida- 4-yl)-1H-indazol- Assay zol-6-yl)-2-(oxazol-6-yl)-2-(oxazol-2- (micromolar) 2-yl)but-3-yn-2-ol yl)but-3-yn-2-ol NIKADP (Ki) 0.0001 0.0003 293-NIK 0.033 0.036 NF-kB-Luciferase (IC₅₀)293-NIK TK 3.1 0.514 Renilla Luciferase (IC₅₀) NIK p52 0.127 0.077Translocation (IC₅₀) NIK RelA >20 >20 Translocation (IC₅₀)

TABLE 16D 1-(2-aminopyrimidin-4-yl)-6- (3-hydroxy-3-(oxazol-2-yl) Assaybut-1-ynyl)-N,N-dimethyl- (micromolar) 1H-indazole-3-carboxamide NIK ADP(Ki) 0.0002 293-NIK 0.051 NF-kB-Luciferase (IC₅₀) 293-NIK TK Renilla0.583 Luciferase (IC₅₀) NIK p52 0.346 Translocation (IC₅₀) NIK RelA >20Translocation (IC₅₀)

We claim:
 1. Compounds of formula (I)

wherein in formula I: Y is nitrogen and the subscript b is the integer0, or Y is carbon and the subscript b is the integer 1; R¹ is C₁₋₂alkyl, C₁₋₂ haloalkyl or —CH₂—OH; R² is C₁₋₆ alkyl, C₁₋₆ haloalkyl, 3-7membered cycloalkyl, C₁₋₆ alkylene-C₃₋₇ membered cycloalkyl, phenyl, 5-6membered heteroaryl, —C(═O)R^(x2a), —C(═O)OR^(x2a) or—C(═O)NR^(x2a)R^(x2b), wherein R^(x2a) is selected from the groupconsisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆heteroalkyl, 3-8 membered cycloalkyl, 3-8 membered heteroalkyl, —(C₁₋₆alkylene)-(3-8 membered cycloalkyl), —(C₁₋₆ alkylene)-(3-8 memberedheterocycloalkyl), —(C₁₋₆ alkylene)-(6-membered aryl) and —(C₁₋₆alkylene)-(5-6 membered heteroaryl) and R^(x2b) is selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl andC₁₋₆ heteroalkyl, and wherein R^(x2a) and R^(x2b), when attached to thesame nitrogen atom, are optionally combined to form a 3-7 memberedheterocycloalkyl further comprising 0-2 additional heteroatoms selectedfrom N, O and S; or alternatively R¹ and R² are combined to form a 3-8membered cycloalkyl or 3-8 membered heterocycloalkyl and optionallyfused thereto is a 5-6 membered heteroaryl ring comprising 1-3heteroatoms selected from N, O and S; and wherein the aliphatic and/oraromatic portions of R¹ and R² either independently or when combined,are optionally substituted with 1 to 5 R^(R1/2) substitutents selectedfrom the group consisting of F, Cl, Br, I, —OH, —NH₂, —SH, —CF₃, —OCF₃,—SF₅, —OCH₃, —(X^(a))₀₋₁—CN, —(X^(a))₀₋₁—NO₂, —(X^(a))₀₋₁—N₃,—(X^(a))₀₋₁—OH, —(X^(a))₀₋₁—H, —(X^(a))₀₋₁—OR^(a),—(X^(a))₀₋₁—N(H)R^(a), —(X^(a))₀₋₁—N(H)₂, —(X^(a))₀₋₁—N(R^(a))₂,—(X^(a))₀₋₁—SR^(a), —(X^(a))₀₋₁—SH, —(X^(a))₀₋₁—C(O)R^(a),—(X^(a))₀₋₁—S(O)₂R^(a), —(X^(a))₀₋₁—S(O)R^(a),—(X^(a))₀₋₁—N(H)S(O)₂R^(a), —(X^(a))₀₋₁—N(R^(a))S(O)₂R^(a),—(X^(a))₀₋₁—OC(O)R^(a), —(X^(a))₀₋₁—N(H)C(O)OR^(a),—(X^(a))₀₋₁—N(R^(a))C(O)OR^(a), —(X^(a))₀₋₁—C(═O)OR^(a),—(X^(a))₀₋₁—C(═O)OH, —(X^(a))₀₋₁—C(═O)N(H)R^(a),—(X^(a))₀₋₁—C(═O)N(R^(a))R^(a), —(X^(a))₀₋₁—N(H)C(═O)R^(a),—(X^(a))₀₋₁—N(R^(a))C(═O)R^(a), —(X^(a))₀₋₁—N(H)C(═O)OR^(a) and—(X^(a))₀₋₁—N(R^(a))C(═O)OR^(a), wherein X^(a) is selected from thegroup consisting of C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene,C₁₋₆ heteroalkylene, 3-6 membered cycloalkylene and 3-6 memberedheterocycloalkylene, and R^(a) at each occurrence is independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆heteroalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3-7 membered cycloalkyl and 3-7membered heterocycloalkyl; A is selected from the group consisting of:

wherein X¹, X² and X³ are independently N or CR⁵, wherein at least oneof X¹, X² and X³ is CR⁵, wherein R⁵ is selected from the groupconsisting of hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, halogen, —OC₁₋₆alkyl, 3-6 membered heterocycloalkyl-C₁₋₃alkyleneoxy-, —CN, —NO₂,—NH(C₁₋₆ alkyl), —NH₂ and —N(C₁₋₆ alkyl)₂; R³ is 5-10 memberedheteroaryl optionally substituted with —NR^(x3a)R^(x3b), wherein R^(x3a)and R^(x3b) are each independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆alkoxy, C₁₋₆ heteroalkyl, 6-10 membered aryl, 5-10 membered heteroaryl,and wherein R³ and the R^(x3a) and R^(x3b) groups of R³, if present, arefurther each independently optionally substituted with 1 to 5 R^(R3)substituents selected from the group consisting of F, Cl, Br, I, —OH,—NH₂, —SH, —CF₃, —OCF₃, —SF₅, —OCH₃, —(X^(b))₀₋₁—CN, —(X^(b))₀₋₁—NO₂,—(X^(b))₀₋₁—N₃, —(X^(b))—OH, —(X^(b))—H, —(X^(b))₀₋₁—OR^(b),—(X^(b))₀₋₁—N(H)R^(b), —(X^(b))—N(H)₂, —(X^(b))₀₋₁—N(R^(b)),—(X^(b))₀₋₁—SR^(b), —(X^(b))₀₋₁—SH, —(X^(b))₀₋₁—C(O)R^(b),—(X^(b))₀₋₁—S(O)₂R^(b), —(X^(B))₀₋₁—S(O)R^(b),—(X^(b))₀₋₁—N(H)S(O)₂R^(b), —(X^(b))₀₋₁—N(R^(b))S(O)₂R^(b),—(X^(b))₀₋₁—OC(O)R^(b), —(X^(b))₀₋₁—N(H)C(O)OR^(b),—(X^(b))₀₋₁—N(R^(b))C(O)OR^(b), —(X^(b))₀₋₁—C(═O)OR^(b),—(X^(b))₀₋₁—C(═O)OH, —(X^(b))₀₋₁—C(═O)N(H)R^(b),—(X^(b))₀₋₁—C(═O)N(R^(b))R^(b), —(X^(b))₀₋₁—N(H)C(═O)R^(b),—(X^(b))₀₋₁—N(R^(b))C(═O)R^(b), —(X^(b))₀₋₁—N(H)C(═O)OR^(b) and—(X^(b))₀₋₁—N(R^(b))C(═O)OR^(b), wherein X^(b) is selected from thegroup consisting of C₁₋₆ alkylene, C₂₋₆ alkenylene, C₂₋₆ alkynylene,C₁₋₆ heteroalkylene, C₃₋₆ cycloalkylene and C₃₋₆ heterocycloalkylene,and R^(b) at each occurrence is independently selected from the groupconsisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆ heteroalkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, 3-7 membered cycloalkyl and 3-7 memberedheterocycloalkyl; R⁴ is -(L)₀₋₁-R^(x4a), wherein L is selected from thegroup consisting of —O—, —N(H)—, —C(═O)—, C₁₋₄ alkylene, C₁₋₄haloalkylene, C₂₋₄ alkenylene, C₂₋₄ alkynylene and C₁₋₄ heteroalkyleneand lea is selected from the group consisting of hydrogen, C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₁₋₆ heteroalkyl, 3-6membered cycloalkyl, 3-9 membered heterocycloalkyl, 6-10 membered aryland 5-10 membered heteroaryl, wherein the aliphatic or aromatic portionsof R⁴ are independently substituted with 0 to 5 R^(R4) substituentsselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆heteroalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylamino, C₁₋₆ dialkylamino, C₃₋₆heterocycloalkyl, F, Cl, Br, I, —OH, —NH₂, —SH, —CF₃, —OCF₃, —SF₅,—(X^(c))₀₋₁—CN, —(X^(c))₀₋₁—NO₂, —(X^(c))₀₋₁—N₃, —(X^(c))—OH,—(X^(c))₀₋₁—OR^(c), —(X^(c))—H, —(X^(c))₀₋₁—R^(c),—(X^(c))₀₋₁—N(H)R^(c), —(X^(c))₀₋₁—N(R^(c))₂, —(X^(c))₀₋₁—SR^(C),—(X^(c))₀₋₁—C(O)R^(c), —(X^(c))₀₋₁—S(O)₂R^(c), —(X^(c))₀₋₁—S(O)R^(c),—(X^(c))₀₋₁—N(H)S(O)₂R^(c), —(X^(c))₀₋₁—N(R^(c))S(O)₂R^(c),—(X^(c))₀₋₁—C(═O)OR^(c), —(X^(c))₀₋₁—C(═O)OH,—(X^(c))₀₋₁—C(═O)N(H)R^(c), —(X^(c))₀₋₁—C(═O)N(R^(c))R^(c),—(X^(c))₀₋₁—N(H)C(═O)R^(c), —(X^(c))₀₋₁—N(R^(c))C(═O)R^(c), whereinX^(c) is selected from the group consisting of C₁₋₆ alkylene, C₂₋₆alkenylene, C₂₋₆ alkynylene, C₁₋₆ heteroalkylene, C₃₋₆ cycloalkylene andC₃₋₆ heterocycloalkylene, and R^(c) at each occurrence is independentlyselected from the group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆heteroalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3-7 membered cycloalkyl, 3-7membered heterocycloalkyl, phenyl and 5-6 membered heteroaryl, whereinany two R^(c) groups attached to the same nitrogen atom are optionallycombined to form a 3-7 membered heterocycloalkyl or 5-10 memberedheteroaryl comprising 1-3 heteroatoms selected from N, O and S.
 2. Thecompound of claim 1, wherein R³ is substituted with —NR^(x3a)R^(x3b),wherein R³ and R^(x3a) and R^(x3b) are optionally substituted with 1 to5 R^(R3) substituents.
 3. The compound of claim 1, wherein Y is nitrogenand the subscript b is the integer
 0. 4. The compound of claim 1,wherein Y is carbon and the subscript b is the integer 1
 5. The compoundof claim 1, wherein A is selected from the group consisting of


6. The compound of claim 1, wherein R³ is selected from the groupconsisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,purinyl, pyrrolopyrimidinyl, triazolopyrimidinyl, pyrazolopyrimidinyl,pyrrolopyrazinyl, pyrazolopyrazinyl, triazolopyrazinyl,imidazolopyrazinyl, pyrrolopyridazinyl, pyrazoloyridazinyl,triazoloyridazinyl, imidazoloyridazinyl, furopyrimidinyl,thienopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrrolyl,imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,isothiazolyl and thiadiazolyl, wherein R³ is substituted with—NR^(x3a)R^(x3b), wherein R³ and the R^(x3a) and R^(x3b) group are eachindependently further optionally substituted with 1 to 5 R^(R3)substituents.
 7. The compound of claim 6, wherein R³ is selected fromthe group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl, pyrrolyl, imidazolyl, pyrazolyl, isoxazolyl, oxadiazolyl,thiazolyl, isothiazolyl and thiadiazolyl and wherein R³ is substitutedwith —NR^(x3a)R^(x3b), wherein R³ and the R^(x3a) and R^(x3b) group arefurther each independently optionally substituted with 1 to 3 R^(R3)substituents.
 8. The compound of claim 7, wherein R^(x3a) and R^(x3b) iseach independently selected from the group consisting of hydrogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆heteroalkyl, 6-10 membered aryl and 5-10 membered heteroaryl, wherein atleast one of R^(x3a) and R^(x3b) is hydrogen.
 9. The compound of claim8, wherein R^(x3a) and R^(x3b) is each independently selected from thegroup consisting of hydrogen, methyl, ethyl, propyl, isopropyl, phenyland pyridyl, and wherein at least one of R^(x3a) and R^(x3b) ishydrogen.
 10. The compound of claim 9, wherein R^(x3a) and R^(x3b) areeach hydrogen.
 11. The compound of claim 7, wherein R^(R3) is selectedfrom the group consisting F, Cl, Br, I, —OH, —NH₂, —CF₃, —OCF₃, —OCH₃,—NO₂, —X^(b)—NO₂, —X^(b)—OH, —X^(b)—H, —X^(b)—OR^(b), —OR^(b),—X^(b)—N(H)R^(b), —N(H)R^(b), —X^(b)—N(H)₂, —X^(b)—N(R^(b)), —N(R^(b))₂,—C(═O)N(H)R^(b), —X^(b)—C(═O)N(H)R^(b), —C(═O)N(R^(b))R^(b),—X^(b)—C(═O)N(R^(b))R^(b), —X^(b)—N(H)C(═O)R^(b), —X^(b)—N(H)C(═O)R^(b),—X^(b)—N(R^(b))C(═O)R^(b) and —N(R^(b))C(═O)R^(b), wherein X^(b) isselected from the group consisting of C₁₋₆ alkylene, C₂₋₆ alkenylene,C₂₋₆ alkynylene, and C₁₋₆ heteroalkylene, and R^(b) at each occurrenceis independently selected from the group consisting of C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₆ heteroalkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, 3-7 memberedcycloalkyl and 3-7 membered heterocycloalkyl.
 12. The compound of claim11, wherein R^(R3) is selected from the group consisting of F, Cl, Br,I, —OH, —NH₂, —CF₃, —OCF₃, —OCH₃, —NO₂, —X^(b)—H, —OR^(b), —N(H)R^(b),—N(R^(b))₂, —C(═O)N(H)R^(b) and —C(═O)N(R^(b))R^(b).
 13. The compound ofclaim 12, wherein R^(R3) is selected from the group consisting of F, Cl,Br, I, —OH, —NH₂, —CF₃, —OCF₃, —OCH₃, —NO₂, —C(═O)N(CH₃)₂ and3-methyloxetan-3yl-(C═O)N(H)—.
 14. The compound of claim 1, wherein R⁴is -(L)₀₋₁-R^(x4a), wherein L is selected from the group consisting of—O—, —N(H)—, —C(═O)—, C₁₋₆ alkylene, C₁₋₆ haloalkylene and C₁₋₆heteroalkylene, R^(x4a) is selected from the group consisting ofhydrogen, 3-6 membered cycloalkyl, 3-9 membered heterocycloalkyl and 5-6membered heteroaryl, wherein the aliphatic and/or aromatic portions ofR⁴ are independently optionally substituted with 1 to 5 R^(R4)substituents.
 15. The compound of claim 14, wherein R⁴ is-(L)₀₋₁-R^(x4a), wherein L is selected from the group consisting of —O—,—N(H)—, —C(═O)—, C₁₋₆ alkylene, C₁₋₆ haloalkylene and C₁₋₆heteroalkylene, R^(x4a) is selected from the group consisting ofhydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl,oxetanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl,tetrahydromorpholinyl, piperidinyl, piperazinyl, thiomorpholino andpyrrolidinyl, wherein the aliphatic and/or aromatic portions of R⁴ areindependently optionally substituted with 1 to 5 R^(R4) substituents.16. The compound of claim 15, wherein R⁴ is selected from the groupconsisting of hydrogen, —C(═O)N(CH₃)₂, —(CH₂)N(CH₃)₂, —(CH₂)N(CH₃)₂,morpholin-4-yl-(CH₂)—, cyclopropylmethyl, trifluoromethylethyl,—CH₂CH₂OCH₃, —OCH₂CH₃, methyl, ethyl, morpholin-4-yl-C(═O)—,pyrrolidin-1-yl-C(═O)—, CH₃OCH₂—, ethoxy and cyclopropyl.
 17. Thecompound of claim 1, wherein R¹ is C₁₋₆ alkyl or C₁₋₆ haloalkyl; R² isC₁₋₆ alkyl, C₁₋₆ haloalkyl, 3-8 membered cycloalkyl, phenyl and 5-6membered heteroaryl; or alternatively R¹ and R² are combined to form a3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl; and whereinthe aliphatic and/or aromatic portions of R¹ and R² either independentlyor when combined, are optionally substituted with 1 to 5 R^(R1/2)substitutents.
 18. The compound of claim 17, wherein R² is selected fromthe group consisting of C₁₋₆ alkyl, C₁₋₆ haloalkyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl,tetrahydropyranyl, thiazolyl, oxadiazolyl, triazolyl, tetrazolyl,oxazolyl, pyrazolyl, pyrimidinyl, pyrazinyl and pyrrolyl; oralternatively R² and R¹ are combined to form 3-6 membered ring selectedfrom the group consisting of cyclobutyl, cyclopentyl, cyclohexyloxetanyl, tetrahydrofuranyl and tetrahydropyanyl, azetidinyl,pyrrolidinyl and piperidinyl, wherein the aliphatic and/or aromaticportions of R¹ and R² either independently or when combined, areoptionally substituted with 1 to 5 R^(R1/2) substituents.
 19. Thecompound of claim 1, wherein formula I has a subformula selected fromthe group consisting of


20. The compound of claim 1, wherein Y is carbon and the subscript b isthe integer 1; R¹ is C₁₋₆ alkyl, C₁₋₆ haloalkyl or CH₂—OH; R² is C₁₋₆alkyl, C₁₋₆ haloalkyl, 3-8 membered cycloalkyl, phenyl and 5-6 memberedheteroaryl; or alternatively R¹ and R² are combined to form a 3-6membered cycloalkyl or 3-6 membered heterocycloalkyl; and wherein thealiphatic and/or aromatic portions of R¹ and R² either independently orwhen combined, are optionally substituted with 1 to 5 R^(R1/2)substitutents; A is selected from the group consisting of

wherein R³ is selected from the group consisting of pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, purinyl,pyrrolopyrimidinyl, triazolopyrimidinyl, pyrazolopyrimidinyl,pyrrolopyrazinyl, pyrazolopyrazinyl, triazolopyrazinyl,imidazolopyrazinyl, pyrrolopyridazinyl, pyrazoloyridazinyl,triazoloyridazinyl, imidazoloyridazinyl, furopyrimidinyl,thienopyrimidinyl, oxazolopyrimidinyl, thiazolopyrimidinyl, pyrrolyl,imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,isothiazolyl and thiadiazolyl, wherein R³ is substituted withNR^(x3a)R^(x3b), wherein R³ and the R^(x3a) and R^(x3b) group are eachindependently further optionally substituted with 1 to 5 R^(R3)substituents; R⁴ is -(L)₀₋₁-R^(x4a), wherein L is selected from thegroup consisting of C(═O)—, C₁₋₆ alkylene, C₁₋₆ haloalkylene and C₁₋₆heteroalkylene, R^(x4a) is selected from the group consisting ofhydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridinyl,oxetanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl,morpholinyl, piperidinyl, piperazinyl, thiomorpholino and pyrrolidinyl,wherein the aliphatic and/or aromatic portions of R⁴ are independentlyoptionally substituted with 1 to 5 R^(R4) substituents; R⁵ is selectedfrom the group consisting of hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl,halogen, —OC₁₋₆ alkyl and 3-6 membered heterocycloalkyl-C₁₋₃alkyleneoxy.
 21. The compound of claim 1, selected from the groupconsisting of:4-(1-(2-aminopyrimidin-4-yl)-1H-indazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-1H-benzo[d]imidazol-5-yl)-2-(thiazol-2-yl)but-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol;1-(2-aminopyrimidin-4-yl)-1H-indazole-6-carbonitrile;4-(1-(2-aminopyrimidin-4-yl)-1H-indazol-6-yl)-2-methylbut-3-yn-2-ol;1-((1-(2-aminopyrimidin-4-yl)-1H-indazol-6-yl)ethynyl)cyclopentanol;4-(1-(2-amino-5-chloropyrimidin-4-yl)-1H-indazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol;1-(2-amino-5-nitropyrimidin-4-yl)-1H-indazole-6-carbonitrile;1-(2,5-diaminopyrimidin-4-yl)-1H-indazole-6-carbonitrile;4-(1-(2-aminopyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl)-2-methylbut-3-yn-2-ol;N-(2-amino-4-(6-cyano-1H-indazol-1-yl)pyrimidin-5-yl)-3-methyloxetane-3-carboxamide;4-(1-(2-aminopyrimidin-4-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-1H-indazol-6-yl)-2-(oxazol-2-yl)but-3-yn-2-ol;N-(2-amino-4-(6-(3-hydroxy-3-(thiazol-2-yl)but-1-ynyl)-1H-indazol-1-yl)pyrimidin-5-yl)-3-methyloxetane-3-carboxamide;4-(1-(2-aminopyrimidin-4-yl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)-2-methylbut-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-3-(morpholinomethyl)-1H-indazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-1H-indazol-6-yl)-1,1-difluoro-2-methylbut-3-yn-2-ol;1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-methylbut-1-ynyl)-1H-benzo[d]imidazol-2(3H)-one;1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-(thiazol-2-yl)but-1-ynyl)-1H-benzo[d]imidazol-2(3H)-one;4-(1-(2-aminopyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl)-2-(oxazol-2-yl)but-3-yn-2-ol;1-(4-(2-methoxypyridin-3-ylamino)-1,3,5-triazin-2-yl)-1H-indazole-6-carbonitrile;4-(1-(4-(2-methoxypyridin-3-ylamino)-1,3,5-triazin-2-yl)-1H-indazol-6-yl)-2-methylbut-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-3-((dimethylamino)methyl)-1H-indazol-6-yl)-2-methylbut-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl)-1,1-difluoro-2-methylbut-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl)-1,1,1-trifluoro-2-methylbut-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-(thiazol-2-yl)but-1-ynyl)-N,N-dimethyl-1H-indazole-3-carboxamide;1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-methylbut-1-ynyl)-N,N-dimethyl-1H-indazole-3-carboxamide;4-(1-(6-(2-methoxypyridin-3-ylamino)pyrimidin-4-yl)-1H-indazol-6-yl)-2-methylbut-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-3-((dimethylamino)methyl)-1H-indazol-6-yl)-2-(oxazol-2-yl)but-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl)-2-(1H-pyrazol-4-yl)but-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl)-2-cyclopropylbut-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-1H-indazol-6-yl)-2-(1H-pyrazol-4-yl)but-3-yn-2-ol;4-(1-(6-aminopyrimidin-4-yl)-1H-indazol-6-yl)-2-methylbut-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl)-1-fluoro-2-methylbut-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-2-ethoxy-1H-benzo[d]imidazol-6-yl)-2-methylbut-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-5-fluoro-1H-benzo[d]imidazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-5-fluoro-1H-benzo[d]imidazol-6-yl)-2-methylbut-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl)-2-(3-methylisoxazol-5-yl)but-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol;1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-(oxazol-2-yl)but-1-ynyl)-N,N-dimethyl-1H-indazole-3-carboxamide;4-(1-(2-aminopyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl)-2-(oxazol-2-yl)but-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-1H-benzo[d]imidazol-6-yl)-2-(oxazol-2-yl)but-3-yn-2-ol;(R)-1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-(thiazol-2-yl)but-1-ynyl)-N,N-dimethyl-1H-indazole-3-carboxamide;(R)-1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-(thiazol-2-yl)but-1-ynyl)-1H-benzo[d]imidazol-2(3H)-one;4-(1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl)-2-(3-methylisoxazol-5-yl)but-3-yn-2-ol;(S)-4-(1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol;4-(1-(4-aminopyrimidin-2-yl)-1H-benzo[d]imidazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl)-2-(4-methylthiazol-2-yl)but-3-yn-2-ol;1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-(3-methylisoxazol-5-yl)but-1-ynyl)-N,N-dimethyl-1H-indazole-3-carboxamide;4-(1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl)-2-(thiazol-5-yl)but-3-yn-2-ol;(R)-4-(1-(2-aminopyrimidin-4-yl)-5-fluoro-3-methyl-1H-indazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl)-2-(5-methylthiazol-2-yl)but-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl)-N,N-dimethyl-1H-indazole-3-carboxamide;4-(1-(4-amino-1,3,5-triazin-2-yl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl)-2-(4-methyl-1,2,5-oxadiazol-3-yl)but-3-yn-2-ol;4-(1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl)-2-(pyrazin-2-yl)but-3-yn-2-ol;(R)-4-(1-(4-amino-1,3,5-triazin-2-yl)-2-cyclopropyl-1H-benzo[d]imidazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol;4-(1-(4-amino-1,3,5-triazin-2-yl)-2-methyl-1H-benzo[d]imidazol-6-yl)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;(1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl)-1H-indazol-3-yl)(morpholino)methanone;(1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl)-1H-indazol-3-yl)(pyrrolidin-1-yl)methanone;4-(1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl)-2-(pyrimidin-2-yl)but-3-yn-2-ol;(R)-4-(1-(4-amino-1,3,5-triazin-2-yl)-2-(methoxymethyl)-1H-benzo[d]imidazol-6-yl)-2-(thiazol-2-yl)but-3-yn-2-ol;4-((1-(2-aminopyrimidin-4-yl)-3-methyl-1H-indazol-6-yl)ethynyl)-1-methylpiperidin-4-ol;4-(1-(2-aminopyrimidin-4-yl)-2-ethoxy-1H-benzo[d]imidazol-6-yl)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;3-(2-aminopyrimidin-4-yl)-5-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-1H-benzimidazol-2-one;(2R)-4-[3-(4-amino-1,3,5-triazin-2-yl)-2-methyl-benzimidazol-5-yl]-2-thiazol-2-yl-but-3-yn-2-ol;4-[1-(2-aminopyrimidin-4-yl)-3-(1-hydroxy-2-methyl-propyl)indazol-6-yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(hydroxymethyl)indazol-6-yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;(2R)-4-[3-(4-amino-1,3,5-triazin-2-yl)-2-methyl-benzimidazol-5-yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;4-[1-(2-aminopyrimidin-4-yl)-3-(1-cyclopropyl-1-hydroxy-ethyl)indazol-6-yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(1-hydroxy-1-methyl-ethyl)indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol;(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(fluoromethyl)indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol;(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(1-hydroxy-1-methyl-ethyl)indazol-6-yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;3-(2-aminopyrimidin-4-yl)-5-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-1-methyl-benzimidazol-2-one;4-[3-(2-aminopyrimidin-4-yl)-2-ethoxy-benzimidazol-5-yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;4-[1-(2-aminopyrimidin-4-yl)-3-methyl-indazol-6-yl]-2-(1H-imidazol-4-yl)but-3-yn-2-ol;3-[1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]benzimidazol-2-yl]oxypropane-1,2-diol;[1-(2-aminopyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]indazol-3-yl]-morpholino-methanone;1-(2-aminopyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-N-methyl-indazole-3-carboxamide;3-[2-[1-(2-aminopyrimidin-4-yl)-3-methyl-indazol-6-yl]ethynyl]-3-hydroxy-1-methyl-pyrrolidin-2-one;4-[3-(2-aminopyrimidin-4-yl)-2-ethoxy-benzimidazol-5-yl]-2-[5-(hydroxymethyl)isoxazol-3-yl]but-3-yn-2-ol;7-[2-[1-(2-aminopyrimidin-4-yl)-3-methyl-indazol-6-yl]ethynyl]-5,6-dihydropyrrolo[1,2-a]imidazol-7-ol;4-[1-(2-aminopyrimidin-4-yl)-3-methyl-indazol-6-yl]-2-[5-(fluoromethyl)isoxazol-3-yl]but-3-yn-2-ol;1-(2-aminopyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]indazole-3-carboxamide;3-(2-aminopyrimidin-4-yl)-5-[3-hydroxy-3-[5-(hydroxymethyl)isoxazol-3-yl]but-1-ynyl]-1H-benzimidazol-2-one;3-(2-aminopyrimidin-4-yl)-5-[2-(7-hydroxy-5,6-dihydropyrrolo[1,2-a]imidazol-7-yl)ethynyl]-1-methyl-benzimidazol-2-one;[1-(2-amino-5-chloro-pyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]indazol-3-yl]-(3-hydroxyazetidin-1-yl)methanone;[1-(2-aminopyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]indazol-3-yl]-(4-fluoro-1-piperidyl)methanone;(2R)-4-[3-(2-aminopyrimidin-4-yl)-2-(oxetan-3-yloxy)benzimidazol-5-yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-[5-(hydroxymethyl)isoxazol-3-yl]but-1-ynyl]-N,N-dimethyl-indazole-3-carboxamide;4-[3-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)benzimidazol-5-yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;7-[2-[3-(2-aminopyrimidin-4-yl)-2-ethoxy-benzimidazol-5-yl]ethynyl]-5,6-dihydropyrrolo[1,2-a]imidazol-7-ol;4-[3-(2-aminopyrimidin-4-yl)-2-(2,2,2-trifluoroethoxy)benzimidazol-5-yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]-N,N-dimethyl-indazole-3-carboxamide;3-(2-aminopyrimidin-4-yl)-5-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]-1-methyl-benzimidazol-2-one;3-(2-aminopyrimidin-4-yl)-1-(cyclopropylmethyl)-5-[3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]benzimidazol-2-one;4-[1-(2-aminopyrimidin-4-yl)-3-methyl-indazol-6-yl]-2-[5-(hydroxymethyl)isoxazol-3-yl]but-3-yn-2-ol;[1-(2-aminopyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]indazol-3-yl]-(3-hydroxyazetidin-1-yl)methanone;(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(1-fluoro-1-methyl-ethyl)indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol;3-[1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]indazol-3-yl]-1,1-difluoro-2-methyl-propan-2-ol;[1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]indazol-3-yl]-morpholino-methanone;(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(morpholinomethyl)indazol-6-yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;1-(2-aminopyrimidin-4-yl)-6-[2-(7-hydroxy-5,6-dihydropyrrolo[1,2-a]imidazol-7-yl)ethynyl]-N,N-dimethyl-indazole-3-carboxamide;(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-(hydroxymethyl)indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol;[1-(2-aminopyrimidin-4-yl)-6-[2-(7-hydroxy-5,6-dihydropyrrolo[1,2-a]imidazol-7-yl)ethynyl]indazol-3-yl]-morpholino-methanone;4-[3-(2-aminopyrimidin-4-yl)-2-tetrahydropyran-4-yloxy-benzimidazol-5-yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;4-[1-(2-aminopyrimidin-4-yl)-3-[(3,3-difluoroazetidin-1-yl)methyl]indazol-6-yl]-2-pyrimidin-2-yl-but-3-yn-2-ol;(2R)-4-[3-(2-aminopyrimidin-4-yl)-2-(2-methoxyethoxy)benzimidazol-5-yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;4-[1-(2-aminopyrimidin-4-yl)-3-methyl-indazol-6-yl]-2-(1H-1,2,4-triazol-3-yl)but-3-yn-2-ol;4-[3-(2-aminopyrimidin-4-yl)-2-(2,2,2-trifluoroethoxy)benzimidazol-5-yl]-2-pyrimidin-2-yl-but-3-yn-2-ol;4-[3-(2-aminopyrimidin-4-yl)-2-(oxetan-3-yloxy)benzimidazol-5-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol;4-[3-(2-aminopyrimidin-4-yl)-2-ethoxy-benzimidazol-5-yl]-2-pyrimidin-2-yl-but-3-yn-2-ol;4-[1-(2-aminopyrimidin-4-yl)-3-(fluoromethyl)indazol-6-yl]-2-pyrimidin-2-yl-but-3-yn-2-ol;(2R)-4-[1-(2-amino-5-chloro-pyrimidin-4-yl)-3-(1-hydroxy-1-methyl-ethyl)indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol;4-[3-(2-aminopyrimidin-4-yl)-2-(2-methoxyethoxy)benzimidazol-5-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol;4-[1-(2-aminopyrimidin-4-yl)-3-methyl-indazol-6-yl]-1-fluoro-2-methyl-but-3-yn-2-ol;[1-(2-aminopyrimidin-4-yl)-6-[2-(7-hydroxy-5,6-dihydrocyclopenta[b]pyridin-7-yl)ethynyl]indazol-3-yl]-morpholino-methanone;[1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]-morpholino-methanone;1-[3-[1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]benzimidazol-2-yl]oxyazetidin-1-yl]ethanone;4-[1-(2-aminopyrimidin-4-yl)-3-(1-hydroxy-1-methyl-ethyl)indazol-6-yl]-2-(2-pyridyl)but-3-yn-2-ol;4-[1-(2-aminopyrimidin-4-yl)-3-(1-hydroxy-1-methyl-ethyl)indazol-6-yl]-2-pyrimidin-2-yl-but-3-yn-2-ol;4-[3-(2-aminopyrimidin-4-yl)-2-(2-methoxyethoxy)benzimidazol-5-yl]-2-pyrimidin-2-yl-but-3-yn-2-ol;4-[1-(2-aminopyrimidin-4-yl)-3-(cyclopropyl-hydroxy-tetrahydropyran-4-yl-methyl)indazol-6-yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;4-[3-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)benzimidazol-5-yl]-2-pyrimidin-2-yl-but-3-yn-2-ol;4-[1-(2-aminopyrimidin-4-yl)-3-(hydroxymethyl)indazol-6-yl]-2-pyrimidin-2-yl-but-3-yn-2-ol;4-[3-(4-amino-1,3,5-triazin-2-yl)-2-methyl-benzimidazol-5-yl]-2-pyrimidin-2-yl-but-3-yn-2-ol;[1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]-(2-oxa-6-azaspiro[3.3]heptan-6-yl)methanone;1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)-N,N-dimethyl-indazole-3-carboxamide;(2R)-4-[1-(2-aminopyrimidin-4-yl)-3-[(3,3-difluoroazetidin-1-yl)methyl]indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol;[1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methanone;7-[2-[1-(2-aminopyrimidin-4-yl)-3-(1-hydroxy-1-methyl-ethyl)indazol-6-yl]ethynyl]-5,6-dihydrocyclopenta[b]pyridin-7-ol;[1-(2-amino-5-chloro-pyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]indazol-3-yl]-(4-fluoro-1-piperidyl)methanone;[1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]-(2,6-dimethylmorpholin-4-yl)methanone;4-[3-(2-aminopyrimidin-4-yl)-2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]benzimidazol-5-yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;[1-(2-amino-5-chloro-pyrimidin-4-yl)-6-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]indazol-3-yl]-(1-piperidyl)methanone;4-[3-(2-aminopyrimidin-4-yl)-2-(oxetan-3-yloxy)benzimidazol-5-yl]-2-pyrimidin-2-yl-but-3-yn-2-ol;4-[1-(2-aminopyrimidin-4-yl)-3-methyl-indazol-6-yl]-2-(1H-pyrazol-3-yl)but-3-yn-2-ol;[1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]-(2,6-dimethylmorpholin-4-yl)methanone;[1-(2-aminopyrimidin-4-yl)-6-(4-fluoro-3-hydroxy-3-methyl-but-1-ynyl)indazol-3-yl]-morpholino-methanone;4-[1-(2-aminopyrimidin-4-yl)-3-methyl-indazol-6-yl]-2-oxazol-4-yl-but-3-yn-2-ol;4-[1-(2-aminopyrimidin-4-yl)-3-(morpholinomethyl)indazol-6-yl]-2-pyrimidin-2-yl-but-3-yn-2-ol;4-[1-(2-aminopyrimidin-4-yl)-3-[(cyclopentylamino)-cyclopropyl-methyl]indazol-6-yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;4-[3-(4-amino-1,3,5-triazin-2-yl)-2-methyl-benzimidazol-5-yl]-2-pyrazin-2-yl-but-3-yn-2-ol;3-(2-aminopyrimidin-4-yl)-1-(cyclopropylmethyl)-5-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]benzimidazol-2-one;1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(3-methyl-1,2,4-oxadiazol-5-yl)but-1-ynyl]-N,N-dimethyl-indazole-3-carboxamide;[1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(1-methyl-1,2,4-triazol-3-yl)but-1-ynyl]indazol-3-yl]-morpholino-methanone;[1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-[5-(methoxymethyl)isoxazol-3-yl]but-1-ynyl]indazol-3-yl]-morpholino-methanone;4-[1-(2-aminopyrimidin-4-yl)-3-[(cyclopentylamino)-cyclopropyl-methyl]indazol-6-yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;[1-(2-aminopyrimidin-4-yl)-6-[4-fluoro-3-(fluoromethyl)-3-hydroxy-but-1-ynyl]indazol-3-yl]-morpholino-methanone;4-[1-[2-amino-5-(1-methylpyrazol-4-yl)pyrimidin-4-yl]indazol-6-yl]-2-methyl-but-3-yn-2-ol;[1-(2-aminopyrimidin-4-yl)-6-[(3S)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]indazol-3-yl]-morpholino-methanone;[1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]-(4-methylpiperazin-1-yl)methanone;4-[1-(2-aminopyrimidin-4-yl)-3-methyl-indazol-6-yl]-2-(1-methylimidazol-2-yl)but-3-yn-2-ol;4-[1-(2-aminopyrimidin-4-yl)-3-methyl-indazol-6-yl]-2-(5-methylpyrazin-2-yl)but-3-yn-2-ol;4-[1-[2-amino-5-(1H-pyrazol-4-yl)pyrimidin-4-yl]indazol-6-yl]-2-methyl-but-3-yn-2-ol;(2R)-4-[1-(2-amino-6-methyl-pyrimidin-4-yl)-3-methyl-indazol-6-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol;4-[1-(2-amino-6-methyl-pyrimidin-4-yl)-3-methyl-indazol-6-yl]-2-pyrimidin-2-yl-but-3-yn-2-ol;4-[1-(2-aminopyrimidin-4-yl)-3-(1-hydroxy-1-methyl-ethyl)indazol-6-yl]-2-(1-methylpyrazol-3-yl)but-3-yn-2-ol;4-[3-(2-aminopyrimidin-4-yl)-2-(oxetan-3-yloxy)benzimidazol-5-yl]-2-methyl-but-3-yn-2-ol;4-[3-(2-aminopyrimidin-4-yl)-2-[1-(2-hydroxyethyl)azetidin-3-yl]oxy-benzimidazol-5-yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;4-[1-(2-aminopyrimidin-4-yl)-3-methyl-indazol-6-yl]-2-(1H-imidazol-2-yl)but-3-yn-2-ol;4-[3-(4-amino-1,3,5-triazin-2-yl)-2-methyl-benzimidazol-5-yl]-1-cyclopropyl-2-methyl-but-3-yn-2-ol;4-[3-(4-amino-1,3,5-triazin-2-yl)-2-methyl-benzimidazol-5-yl]-2-methyl-but-3-yne-1,2-diol;(2R)-4-[1-[2-(methylamino)pyrimidin-4-yl]indazol-6-yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;4-[1-(2-aminopyrimidin-4-yl)-3-methyl-indazol-6-yl]-2-hydroxy-1-(3-hydroxyazetidin-1-yl)-2-methyl-but-3-yn-1-one;4-[1-(2-aminopyrimidin-4-yl)-3-methyl-indazol-6-yl]-2-hydroxy-N,N,2-trimethyl-but-3-ynamide[1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]benzimidazol-2-yl]-pyrrolidin-1-yl-methanone;[1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]indazol-3-yl]-morpholino-methanone;1-[2-[3-(4-amino-1,3,5-triazin-2-yl)-2-methyl-benzimidazol-5-yl]ethynyl]cyclohexanol;[1-[2-[3-(4-amino-1,3,5-triazin-2-yl)-2-methyl-benzimidazol-5-yl]ethynyl]cyclopentyl]methanol;4-[3-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)benzimidazol-5-yl]-2-(5-fluoro-2-pyridyl)but-3-yn-2-ol;3-[3-[3-(4-amino-1,3,5-triazin-2-yl)-2-methyl-benzimidazol-5-yl]-1-hydroxy-prop-2-ynyl]cyclobutanol;2-[2-[3-(4-amino-1,3,5-triazin-2-yl)-2-methyl-benzimidazol-5-yl]ethynyl]norbornan-2-ol;4-[3-(4-amino-1,3,5-triazin-2-yl)-2-methyl-benzimidazol-5-yl]-2-[4-(hydroxymethyl)thiazol-2-yl]but-3-yn-2-ol;2-[2-[3-[3-(4-amino-1,3,5-triazin-2-yl)-2-methyl-benzimidazol-5-yl]-1-hydroxy-1-methyl-prop-2-ynyl]thiazol-4-yl]acetonitrile;3-[2-[3-(4-amino-1,3,5-triazin-2-yl)-2-methyl-benzimidazol-5-yl]ethynyl]-3-hydroxy-cyclobutanecarbonitrile;3-[2-[3-(4-amino-1,3,5-triazin-2-yl)-2-methyl-benzimidazol-5-yl]ethynyl]tetrahydropyran-3-ol;1-[2-[3-(4-amino-1,3,5-triazin-2-yl)-2-methyl-benzimidazol-5-yl]ethynyl]-3-(hydroxymethyl)cyclobutanol;3-[2-[3-(4-amino-1,3,5-triazin-2-yl)-2-methyl-benzimidazol-5-yl]ethynyl]oxetan-3-ol;1-(2-aminopyrimidin-4-yl)-6-[2-(7-hydroxy-5,6-dihydropyrrolo[1,2-c]imidazol-7-yl)ethynyl]-N,N-dimethyl-indazole-3-carboxamide;4-[3-(4-amino-1,3,5-triazin-2-yl)-2-methyl-benzimidazol-5-yl]-2,2-dimethyl-but-3-yn-1-ol;4-[1-[4-(methylamino)pyrimidin-2-yl]indazol-6-yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;1-[2-[1-(2-aminopyrimidin-4-yl)-4-fluoro-indazol-6-yl]ethynyl]cyclopentanol;[1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-pyrimidin-4-yl-but-1-ynyl)indazol-3-yl]-morpholino-methanone;(2R)-4-[3-(2-aminopyrimidin-4-yl)-2-(2-fluoroethoxy)benzimidazol-5-yl]-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol;4-[3-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)benzimidazol-5-yl]-2-(5-chloro-2-pyridyl)but-3-yn-2-ol;4-[3-(2-aminopyrimidin-4-yl)-2-(2-fluoroethoxy)benzimidazol-5-yl]-2-pyrimidin-2-yl-but-3-yn-2-ol;4-[1-(2-aminopyrimidin-4-yl)-3-methyl-indazol-6-yl]-2-thiazol-2-yl-but-3-yn-2-ol;4-[3-(4-amino-1,3,5-triazin-2-yl)-2-methyl-benzimidazol-5-yl]-2-methyl-1-pyrazol-1-yl-but-3-yn-2-ol;(2R)-4-[3-(2-aminopyrimidin-4-yl)-2-(2-methoxyethylamino)benzimidazol-5-yl]-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol;7-[2-[1-(2-aminopyrimidin-4-yl)-3-methyl-indazol-6-yl]ethynyl]-5,6-dihydropyrrolo[1,2-a]imidazol-7-ol;4-[1-(2-aminopyrimidin-4-yl)-3-methyl-indazol-6-yl]-2-[1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]but-3-yn-2-ol;[1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]-morpholino-methanone;4-[3-(2-aminopyrimidin-4-yl)-2-(2-methoxyethylamino)benzimidazol-5-yl]-2-(4-methylthiazol-2-yl)but-3-yn-2-ol;[1-(2-aminopyrimidin-4-yl)-6-[2-(7-hydroxy-5,6-dihydrocyclopenta[b]pyridin-7-yl)ethynyl]indazol-3-yl]-morpholino-methanone;4-[3-(2-aminopyrimidin-4-yl)-2-(2-hydroxyethoxy)benzimidazol-5-yl]-2-(5-chloro-2-pyridyl)but-3-yn-2-ol;1-(2-aminopyrimidin-4-yl)-N-(cyanomethyl)-6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazole-3-carboxamide;[1-(2-aminopyrimidin-4-yl)-6-[2-(7-hydroxy-5,6-dihydrocyclopenta[b]pyridin-7-yl)ethynyl]indazol-3-yl]-morpholino-methanone;3-[2-[1-(2-aminopyrimidin-4-yl)-3-methyl-indazol-6-yl]ethynyl]-3-hydroxy-1-methyl-piperidin-2-one;[1-(2-aminopyrimidin-4-yl)-6-[3-hydroxy-3-(5-methyl-1,3,4-oxadiazol-2-yl)but-1-ynyl]indazol-3-yl]-morpholino-methanone;1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)-N-(2-methoxyethyl)-N-methyl-indazole-3-carboxamide;[1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]-(3,3-difluoroazetidin-1-yl)methanone;[1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]-(3-azabicyclo[3.1.0]hexan-3-yl)methanone;[1-(2-aminopyrimidin-4-yl)-6-[2-(7-hydroxy-5,6-dihydrocyclopenta[b]pyridin-7-yl)ethynyl]indazol-3-yl]-morpholino-methanone;1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)-N-methyl-N-(2-pyridyl)indazole-3-carboxamide;1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)-N-(3-pyridyl)indazole-3-carboxamide;[1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-oxazol-2-yl-but-1-ynyl)indazol-3-yl]-morpholino-methanone;[1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]-(3-hydroxy-1-piperidyl)methanone;[1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]-(3-hydroxyazetidin-1-yl)methanone;1-[1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazole-3-carbonyl]azetidine-3-carbonitrile;1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)-N-(oxetan-3-yl)indazole-3-carboxamide;[1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]-morpholino-methanone;[1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl)indazol-3-yl]-morpholino-methanone;[1-(2-aminopyrimidin-4-yl)-6-(3-hydroxy-3-oxazol-2-yl-but-1-ynyl)indazol-3-yl]-(3-hydroxyazetidin-1-yl)methanone;and7-[2-[3-(2-aminopyrimidin-4-yl)-2-ethoxy-benzimidazol-5-yl]ethynyl]-5,6-dihydrocyclopenta[b]pyridin-7-ol.22. A pharmaceutical composition comprising a compound of claim 1 and atleast one pharmaceutically acceptable carrier, diluent or excipient. 23.A method for the treatment of an inflammatory condition, wherein saidmethod comprises administering an effective amount of a compound asdefined in claim
 1. 24. The method of claim 23, wherein saidinflammatory condition is selected from the group consisting of asthma,lupus, COPD, rhinitis, multiple sclerosis, IBD, arthritis, rheumatoidarthritis, dermatisis, endometriosis and transplant rejection.
 25. Amethod for the treatment of lymphoma, leukemia or multiple myeloma,wherein said method comprises administering an effective amount of acompound as defined in claim 1.